Therapeutic compounds

ABSTRACT

Compounds of formula I: 
     
       
         
         
             
             
         
       
     
     or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. Nos. 61/771,655, filed Mar. 1, 2013 and61/857,636, filed Jul. 23, 2013, the disclosures of each of which arehereby incorporated herein by reference in their entirety.

BACKGROUND

Positive-single stranded RNA viruses comprising the Retroviridae familyinclude those of the subfamily Orthoretrovirinae and generaAlpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus,Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human andanimal diseases. Among the Lentivirus, HIV-1 infection in humans leadsto depletion of T helper cells and immune dysfunction, producingimmunodeficiency and vulnerability to opportunistic infections. TreatingHIV-1 infections with highly active antiretroviral therapies (HAART) hasproven to be effective at reducing viral load and significantly delayingdisease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570).However, these treatments could lead to the emergence of HIV strainsthat are resistant to current therapies (Taiwo, B., InternationalJournal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al.,Science 2010, 327:697-701). Therefore, there is a pressing need todiscover new antiretroviral agents that are active against emergingdrug-resistant HIV variants.

SUMMARY

Provided herein are compounds and methods for the treatment of HIV(i.e., human immunodeficiency virus) infection.

One embodiment provides a compound of formula IIId:

wherein

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are thesame or different;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2C) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)COR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6);

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

each Z⁵ is independently halogen, which may be same or different; and

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

One embodiment provides a compound of formula III:

wherein

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 or 2 Z³ groups, wherein the Z³ groups are the same or different;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different;

R² is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogen, whichare the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are thesame or different;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl, or(C₁-C₄)haloalkyl;

each Z^(2c) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl or halogen;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6); and

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

or a pharmaceutically acceptable salt thereof.

One embodiment provides a compound of formula I

wherein:

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith one or more (e.g., 1 or 2) Z³ groups;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl or3-12 membered heterocycle of R¹ is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁴ groups;

R² is phenyl, 5-membered monocyclic-heteroaryl, 6-memberedmonocyclic-heteroaryl or (C₃-C₇)carbocycle, wherein any phenyl,5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or(C₃-C₇)carbocycle of R² is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁵ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl, or R^(3a) is selected from H,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl and R^(3b) is selected from —OH and—CN;

Z¹ is selected from 6-12 membered aryl, 5-14 membered heteroaryl and3-14 membered heterocycle, wherein any 6-12 membered aryl, 5-14 memberedheteroaryl and 3-14 membered heterocycle of Z¹ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b);

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n1), —OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1),—S(O)R^(p1), —S(O)₂OH, —S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1),—NR^(q1)R^(r1), —NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1),—NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂OR^(p1),—NR^(n1)S(O)₂NR^(q1)R^(r1), NO₂, —C(O)R^(n1), —C(O)OR^(n1),—C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12membered heterocycle of Z^(1a) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(1c) is independently selected from (C₃-C₇)carbocycle, phenyl,5-6 membered monocyclic-heteroaryl, 3-7 membered heterocycle, halogen,—CN, —OR^(n2), —OC(O)R^(p2), —OC(O)NR^(q2)R^(r2), —SR^(n2), —S(O)R^(p2),—S(O)₂OH, —S(O)₂R^(p2), —S(O)₂NR^(q2)R^(r2), —NR^(q2)R^(r2),—NR^(n2)COR^(p2), —NR^(n2)CO₂R^(p2), —NR^(n2)CONR^(q2)R^(r2),—NR^(n2)S(O)₂R^(p2), —NR^(n2)S(O)₂OR^(p2), —NR^(n2)S(O₂NR^(q2)R^(r2),NO₂, —C(O)R^(n2), —C(O)OR^(n2), —C(O)NR^(q2)R^(r2), halophenyl, 5-6membered haloheteroaryl, 3-7 membered haloheterocycle and(C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R^(n1) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(n1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(n1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

each R^(p1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(p1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(p1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

R^(q1) and R^(r1) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(q1) or R^(r1) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d)groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynylof R^(q1) or R^(r1) is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1c) groups, or R^(q1) and R^(r1) together with thenitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle, wherein the 5, 6 or 7-membered heterocycle is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d)groups;

each R^(n2) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R^(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 memberedmonocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

R^(q2) and R^(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R^(q2) and R^(r2) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

Z² is selected from (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,—C(O)R^(n3) and —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12membered C-linked-heteroaryl and 3-12 membered C-linked-heterocycle ofZ² is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4, or 5) Z^(2c) groups;

each Z^(2a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n4), —OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4),—S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4),—NR^(q4)R^(r4), —NR^(n4)COR^(p4), —NR^(n4)CO₂R^(p4),—NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4), —NR^(n4)S(O)₂OR^(p4),—NR^(n4)S(O)₂NR^(q4)R^(r4), NO₂, —C(O)R^(n4), —C(O)OR^(n4) and—C(O)NR^(q4)R^(r4), wherein any (C₃-C₇)carbocycle, 6-12 membered aryl,5-12 membered heteroaryl and 3-12 membered heterocycle of Z^(2a) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b)or Z^(2c) groups;

each Z^(2b) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z^(2c) is independently selected from halogen, —CN, —OR^(n4),—OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH,—S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), NO₂, —C(O)R^(n4),—C(O)OR^(n4) and —C(O)NR^(q4)R^(r4);

each R^(r3) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(n3) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₁-C₄)alkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl of R^(n3) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a) groups;

R^(q3) and R^(r3) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(q3) or R^(r3) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, andwherein any (C₁-C₄)alkyl and (C₂-C₄)alkenyl of R^(q3) or R^(r3) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a)groups, or R^(q3) and R^(r3) together with the nitrogen to which theyare attached form a heterocycle or heteroaryl, wherein the heterocycleor heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3,4 or 5) Z^(2b) or Z^(2c) groups;

each R^(n4) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each R^(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

R^(q4) and R^(r4) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each Z³ is independently selected from halogen, (C₁-C₄)alkyl, —OH, —CN,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, halogen, —CN, —OR^(n5), —OC(O)R^(p5),—OC(O)NR^(q5)R^(r5), —SR^(n5), —S(O)R^(p5), —S(O)₂OH, —S(O)₂R^(p5),—S(O)₂NR^(q5)R^(r5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5),—NR^(n5)CO₂R^(p5), —NR^(n5)CONR^(q5)R^(r5), —NR^(n5)S(O)₂R^(p5),—NR^(n5)S(O)₂OR^(p5), —NR^(n5)S(O)₂NR^(q5)R^(r5), NO₂, —C(O)R^(n5),—C(O)OR^(n5) and —C(O)NR^(q5)R^(r5), wherein any (C₃-C₇)carbocycle, ofZ⁴ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(4a) or Z^(4b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of Z⁴ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(4a) groups;

each Z^(4a) is independently selected from halogen, —CN, —OR^(n6),—OC(O)R^(p6), —OC(O)NR^(q6)R^(r6), —SR^(n6), —S(O)R^(p6), —S(O)₂OH,—S(O)₂R^(p6), —S(O)₂NR^(q6)R^(r6), —NR^(q6)R^(r6), —NR^(n6)COR^(p6),—NR^(n6)CO₂R^(p6), —NR^(n6)CONR^(q6)R^(r6), —NR^(n6)S(O)₂R^(p6),—NR^(n6)S(O)₂OR^(p6), —NR^(n6)S(O)₂NR^(q6)R^(r6), NO₂, —C(O)R^(n6),—C(O)OR^(n6) and —C(O)NR^(q6)R^(r6);

each Z^(4b) is independently selected from (C₁-C₄)alkyl, (C₂-C₄)alkenyl(C₂-C₄)alkynyl and (C₁-C₄)haloalkyl;

each R^(n5) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p5) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q5) and R^(r5) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(n6) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p6) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q6) and R^(r6) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each Z⁵ is independently selected from (C₁-C₆)alkyl, halogen, —CN and—OR^(n7), wherein any (C₁-C₆)alkyl of Z⁵ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) halogen; and

each R^(n7) is independently selected from H, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl and (C₃-C₇)carbocycle;

or a pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier. Another embodiment provides apharmaceutical composition comprising a compound as detailed herein,including a compound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, andIIIk, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

One embodiment provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof; andan additional therapeutic agent, wherein the additional therapeuticagent is an HIV protease inhibiting compound, an HIV non-nucleosideinhibitor of reverse transcriptase, an HIV nucleoside inhibitor ofreverse transcriptase, an HIV nucleotide inhibitor of reversetranscriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerizationinhibitor, or a non-catalytic site HIV integrase inhibitor andcombinations thereof. Another embodiment provides a pharmaceuticalcomposition comprising a compound of any one of formulas I, Ia, Ib, Ic,Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh,IIIi, IIIj, and IIIk, or a pharmaceutically acceptable salt thereof; andan additional therapeutic agent, wherein the additional therapeuticagent is an HIV protease inhibiting compound, an HIV non-nucleosideinhibitor of reverse transcriptase, an HIV nucleoside inhibitor ofreverse transcriptase, an HIV nucleotide inhibitor of reversetranscriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerizationinhibitor, or a non-catalytic site HIV integrase inhibitor andcombinations thereof.

One embodiment provides a method for treating a Retroviridae viralinfection (e.g., an HIV viral infection) in a mammal (e.g., a human),comprising administering a compound of formula I, or a pharmaceuticallyacceptable salt thereof, to the mammal. Another embodiment provides amethod for treating a Retroviridae viral infection (e.g., an HIV viralinfection) in a mammal (e.g., a human), comprising administering acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf,IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable saltthereof, to the mammal. Another embodiment provides a method fortreating a HIV infection in a patient in need thereof comprisingadministering a therapeutically effective amount of a compound asdetailed herein, or a pharmaceutically acceptable salt thereof, to thepatient.

One embodiment provides a method for inhibiting the proliferation of theHIV virus, treating AIDS or delaying the onset of AIDS or ARC symptomsin a mammal (e.g., a human), comprising administering a compound offormula I, or a pharmaceutically acceptable salt thereof, to the mammal.Another embodiment provides a method for inhibiting the proliferation ofthe HIV virus, treating AIDS or delaying the onset of AIDS or ARCsymptoms in a mammal (e.g., a human), comprising administering acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf,IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable saltthereof, to the mammal.

One embodiment provides a method for treating an HIV infection in amammal (e.g., a human), comprising administering a compound of formulaI, or a pharmaceutically acceptable salt thereof, to the mammal. Anotherembodiment provides a method for treating an HIV infection in a mammal(e.g., a human), comprising administering a compound as detailed herein,including a compound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, andIIIk, or a pharmaceutically acceptable salt thereof, to the mammal.

One embodiment provides a method for treating an HIV infection in amammal (e.g., a human), comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of formula I,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof. Another embodiment provides a method for treatingan HIV infection in a mammal (e.g., a human), comprising administeringto the mammal in need thereof a therapeutically effective amount of acompound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III,IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, ora pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof. Another embodiment provides a method for treatingan HIV infection in a patient in need thereof comprising administeringto the patient a therapeutically effective amount of a compound asdescribed herein, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of an additionaltherapeutic agent, wherein the additional therapeutic agent is an HIVprotease inhibiting compound, an HIV non-nucleoside inhibitor of reversetranscriptase, an HIV nucleoside inhibitor of reverse transcriptase, anHIV nucleotide inhibitor of reverse transcriptase, an HIV integraseinhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, aCCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalyticsite HIV integrase site inhibitor and combinations thereof.

One embodiment provides a method for treating an HIV infection in amammal (e.g., a human), comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of formula I,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and non-catalytic site HIV integraseinhibitors, and combinations thereof. Another embodiment provides amethod for treating an HIV infection in a mammal (e.g., a human),comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound as detailed herein, including a compoundof any one of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb,IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and non-catalytic site HIV integraseinhibitors, and combinations thereof.

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof for use in medical therapy (e.g., for use intreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human)). Another embodimentprovides a compound as detailed herein, including a compound of any oneof formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId,IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceuticallyacceptable salt thereof, for use in medical therapy (e.g., for use intreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human)).

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof for use in the manufacture of a medicament fortreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human). Another embodimentprovides a compound as detailed herein, including a compound of any oneof formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId,IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceuticallyacceptable salt thereof, for use in the manufacture of a medicament fortreating a Retroviridae viral infection (e.g., an HIV viral infection)or the proliferation of the HIV virus or AIDS or delaying the onset ofAIDS or ARC symptoms in a mammal (e.g., a human).

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof, for use in the prophylactic or therapeutictreatment of the proliferation of a Retroviridae virus, an HIV virus orAIDS or for use in the therapeutic treatment of delaying the onset ofAIDS or ARC symptoms. Another embodiment provides a compound as detailedherein, including a compound of any one of formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi,IIIj, and IIIk, or a pharmaceutically acceptable salt thereof, for usein the prophylactic or therapeutic treatment of the proliferation of aRetroviridae virus, an HIV virus or AIDS or for use in the therapeutictreatment of delaying the onset of AIDS or ARC symptoms.

One embodiment provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof, for use in the prophylactic or therapeutictreatment of a Retroviridae virus infection (e.g., an HIV virusinfection). Another embodiment provides a compound as detailed herein,including a compound of any one of formulas I, Ia, Ib, Ic, Id, Ie, If,Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, andIIIk, or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of a Retroviridae virus infection(e.g., an HIV virus infection).

One embodiment provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for a Retroviridae virus infection (e.g., an HIV virusinfection) in a mammal (e.g., a human). Another embodiment provides acompound as detailed herein, including a compound of any one of formulasI, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf,IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for a Retroviridae virusinfection (e.g., an HIV virus infection) in a mammal (e.g., a human).

One embodiment provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.Another embodiment provides processes and intermediates disclosed hereinthat are useful for preparing compounds of any one of formulas I, Ia,Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg,IIIh, IIIi, IIIj, and IIIk, or salts thereof.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience only and are not to be construedto limit the claims in any way. Embodiments illustrated under anyheading may be combined with embodiments illustrated under any otherheading.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience; chemical groups may be depicted with or without one or moredashes without losing their ordinary meaning. A wavy line drawn througha line in a structure indicates a point of attachment of a group. Adashed line indicates an optional bond. A prefix such as “C_(u-v)” or(C_(u)-C_(v)) indicates that the following group has from u to v carbonatoms. For example, “C₁₋₆alkyl” indicates that the alkyl group has from1 to 6 carbon atoms.

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Alkyl” is a straight or branched saturated hydrocarbon. For example, analkyl group can have 1 to 8 carbon atoms (i.e., (C₁-C₈)alkyl) or 1 to 6carbon atoms (i.e., (C₁-C₆ alkyl) or 1 to 4 carbon atoms (i.e.,(C₁-C₄)alkyl). Examples of suitable alkyl groups include, but are notlimited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr,n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl(n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkenyl” is a straight or branched hydrocarbon with at least onecarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkenyl). Examples of suitable alkenyl groups include, but are notlimited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂) and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a straight or branched hydrocarbon with at least onecarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 8 carbon atoms (i.e., C₂-C₈ alkyne,) or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkynyl). Examples of suitable alkynyl groups include, but are notlimited to, acetylenic (—C≡CH), propargyl (—CH₂C≡CH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl are eachindependently replaced by a halo substituent. For example,(C₁-C₆)haloalkyl is a (C₁-C₆)alkyl wherein one or more of the hydrogenatoms of the (C₁-C₆)alkyl have been replaced by a halo substituent.Examples of haloalkyls include but are not limited to fluoromethyl,fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1, trifluoroethyl and pentafluoroethyl.

The term “heteroalkyl” as used herein refers to an alkyl as definedherein, wherein one or more of the carbon atoms of the alkyl arereplaced by an O, S, or NR^(q), (or if the carbon atom being replaced isa terminal carbon with an OH, SH or N(R^(q))₂) wherein each R^(q) isindependently H or (C₁-C₆)alkyl. For example, (C₁-C₈)heteroalkylincludes a heteroalkyl of one to eight carbons and one or moreheteroatoms (e.g., O, S, NR^(q), OH, SH or N(R^(q))₂). Thus, forexample, a C₁ heteroalkyl encompasses, e.g., —CH₂—NH₂. Examples ofheteroalkyls include but are not limited to methoxymethyl, ethoxymethyl,methoxy, 2-hydroxyethyl and N,N′-dimethylpropylamine.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. It is also tobe understood that when reference is made to a certain atom-rangemembered aryl (e.g., 6-12 membered aryl), the atom range is for thetotal ring atoms of the aryl. For example, a 6-membered aryl wouldinclude phenyl and a 10-membered aryl would include naphthyl and1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groupsinclude, but are not limited to, phenyl, indenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (toform for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (toform for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form forexample indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isalso to be understood that the point of attachment of a multiplecondensed ring system (as defined above for a heteroaryl) can be at anyposition of the multiple condensed ring system including a heteroaryl,heterocycle, aryl or carbocycle portion of the multiple condensed ringsystem. It is also to be understood that the point of attachment for aheteroaryl or heteroaryl multiple condensed ring system can be at anysuitable atom of the heteroaryl or heteroaryl multiple condensed ringsystem including a carbon atom and a heteroatom (e.g., a nitrogen). Italso to be understood that when a reference is made to a certainatom-range membered heteroaryl (e.g., a 5-14 membered heteroaryl), theatom range is for the total ring atoms of the heteroaryl and includescarbon atoms and heteroatoms. For example, a 5-membered heteroaryl wouldinclude a thiazolyl and a 10-membered heteroaryl would include aquinolinyl. Exemplary heteroaryls include but are not limited topyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “C-linked-heteroaryl” (carbon-linked heteroaryl) as used hereinrefers to a heteroaryl that is linked at a carbon atom of the heteroarylto the remainder of the compound of formula I (e.g., aC-linked-heteroaryl of Z² bonded to the A ring of formula I through acarbon atom of the C-linked-heteroaryl).

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Exemplary heterocycles include but are not limited toazetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. It is also to be understood that the point of attachment ofa multiple condensed ring system (as defined above for a heterocycle)can be at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). It is also to beunderstood that when reference is made to a certain atom-range memberedheterocycle (e.g., a 3-14 membered heterocycle), the atom range is forthe total ring atoms of the heterocycle and includes carbon atoms andheteroatoms. For example, a 3-membered heterocycle would include anaziridinyl and a 10-membered heterocycle would include a1,2,3,4-tetrahydroquinolyl. Exemplary heterocycles include, but are notlimited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one and pyrrolidin-2-one.

The term “C-linked-heterocycle” (carbon-linked heterocycle) as usedherein refers to a “heterocycle that is linked at a carbon atom of theheterocycle to the remainder of the compound of formula I (e.g., aC-linked-heterocycle of Z² bonded to the A ring of formula I through acarbon atom of the C-linked-heterocycle).

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e., (C₃-C₇)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 carbon atoms). The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Forexample, multicyclic carbocyles can be connected to each other via asingle carbon atom to form a spiro connection (e.g., spiropentane,spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fusedconnection (e.g., carbocycles such as decahydronaphthalene, norsabinane,norcarane) or via two non-adjacent carbon atoms to form a bridgedconnection (e.g., norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” can also be optionally substituted withone or more (e.g., 1, 2 or 3) oxo groups. Non-limiting examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

The term “halophenyl” as used herein refers to phenyl, wherein one ormore (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of the phenyl are eachreplaced independently by a halo substituent. Examples of halophenylinclude but are not limited to fluorophenyl, 2,3-dichlorophenyl,3-bromo-4-fluorophenyl and pentafluorophenyl.

The term “haloheteroaryl” as used herein refers to a heteroaryl, whereinone or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of the heteroaryl areeach replaced independently by a halo substituent. Examples ofhaloheteroaryl include but are not limited to 2-fluorofuryl,2,3-dichloropyridinyl and 8-chloro-3-fluoroquinolinyl.

The term “haloheterocycle” as used herein refers to a heterocycle,wherein one or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms of theheterocycle are each replaced independently by a halo substituent.Examples of haloheteroaryl include but are not limited to2-fluoropiperidinyl, 2-chloro-3-fluoropiperazinyl and3-bromopyrrolidinyl.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention. Similarly, one skilled in the art willrecognize that substituents and other moieties of the compounds detailedherein, including a compound of any one of formulas I, Ia, Ib, Ic, Id,Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi,IIIj, and IIIk, or a pharmaceutically acceptable salt thereof, should beselected in order to provide a compound which is sufficiently stable toprovide a pharmaceutically useful compound which can be formulated intoan acceptably stable pharmaceutical composition. Compounds as detailedherein which have such stability are contemplated as falling within thescope of the present invention.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity). The word “about” may also be representedsymbolically by “˜” in the context of a chemical measurement (e.g., ˜50mg or pH ˜7).

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

In one embodiment, “treatment” or “treating” include one or more of thefollowing: a) inhibiting the disease or condition (e.g., decreasing oneor more symptoms resulting from the disease or condition, and/ordiminishing the extent of the disease or condition); b) slowing orarresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition); andc) relieving the disease or condition, e.g., causing the regression ofclinical symptoms, ameliorating the disease state, delaying theprogression of the disease, increasing the quality of life, and/orprolonging survival.

Stereoisomers

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their minorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axesof chirality and whose molecules are not mirror images of one another.Diastereomers typically have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable minor images of one another.

The compounds disclosed herein may have chiral centers, e.g., chiralcarbon atoms. Such compounds thus include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers.In addition, the compounds disclosed herein include enriched or resolvedoptical isomers at any or all asymmetric, chiral atoms. Similarly,compositions disclosed herein also include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers ofcompounds disclosed herein. In addition, the compounds and compositionsdisclosed herein include enriched or resolved optical isomers at any orall asymmetric, chiral atoms. In other words, the chiral centersapparent from the depictions are provided as the chiral isomers orracemic mixtures. Both racemic and diastereomeric mixtures, as well asthe individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention. The racemic mixtures can be separated intotheir individual, substantially optically pure isomers throughwell-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.The desired optical isomer can also be synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

The invention includes any or all of the stereochemical forms, includingany enantiomeric or diastereomeric forms and geometric isomers of thecompounds described, or mixtures thereof. Unless stereochemistry isexplicitly indicated in a chemical structure or name, the structure orname is intended to embrace all possible stereoisomers, includinggeometric isomers, of a compound depicted. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical form,including a specific geometric isomer, thereof. Compositions comprisinga mixture of compounds of the invention in any ratio are also embracedby the invention, including mixtures of two or more stereochemical formsof a compound of the invention in any ratio, such that racemic,non-racemic, enantio-enriched and scalemic mixtures of a compound areembraced, or mixtures thereof.

It is to be understood that for compounds disclosed herein when a bondis drawn in a non-stereochemical manner (e.g., flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom towhich the stereochemical bond is attached has the stereochemistry asshown unless otherwise noted. Accordingly, in one embodiment, a compounddisclosed herein is greater than 50% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 80% a singleenantiomer. In another embodiment, a compound disclosed herein is atleast 90% a single enantiomer. In another embodiment, a compounddisclosed herein is at least 98% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 99% a singleenantiomer. In another embodiment, a compound disclosed herein isgreater than 50% a single diastereomer. In another embodiment, acompound disclosed herein is at least 80% a single diastereomer. Inanother embodiment, a compound disclosed herein is at least 90% a singlediastereomer. In another embodiment, a compound disclosed herein is atleast 98% a single diastereomer. In another embodiment, a compounddisclosed herein is at least 99% a single diastereomer.

Accordingly, in one embodiment, a composition disclosed herein isgreater than 50% a single enantiomer. In another embodiment, acomposition disclosed herein is at least 80% a single enantiomer. Inanother embodiment, a composition disclosed herein is at least 90% asingle enantiomer. In another embodiment, a composition disclosed hereinis at least 98% a single enantiomer. In another embodiment, acomposition disclosed herein is at least 99% a single enantiomer. Inanother embodiment, a composition disclosed herein is greater than 50% asingle diastereomer. In another embodiment, a composition disclosedherein is at least 80% a single diastereomer. In another embodiment, acomposition disclosed herein is at least 90% a single diastereomer. Inanother embodiment, a composition disclosed herein is at least 98% asingle diastereomer. In another embodiment, a composition disclosedherein is at least 99% a single diastereomer.

In certain embodiments, the compounds disclosed herein displayatropisomerism resulting from steric hindrance affecting the axialrotation rate around a single bond. In certain circumstances, theresultant conformational isomers are observed as distinct entities bycharacterization techniques such as NMR and HPLC. In certainembodiments, the compounds disclosed herein exist as a mixture ofatropisomers. The synthetic examples provided herein note where suchmixtures of atropisomers have been observed. However, the detection ofatropisomers is dependent on factors such as temperature, solvent,conditions of purification, and timescale of spectroscopic technique.Characterization data presented herein may not represent the equilibriumstate depending on the conditions of purification, isolation, handling,solvents used, and temperature.

Tautomers

The compounds disclosed herein can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.Another non-limiting example includes keto-enol tautomers ofheteroaryls. Such tautomers are exemplified by T1/T1′, T2/T2′ andT3/T3′. All such tautomeric forms are also within the scope of theinvention.

Protecting Groups

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Salts and Hydrates

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Pharmaceutically acceptable salts are generallyregarded as safe and suitable for use without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio. Examples of “pharmaceutically acceptablesalts” of the compounds disclosed herein include salts derived from anappropriate base, such as an alkali metal (for example, sodium), analkaline earth metal (for example, magnesium), ammonium and NX₄ ⁺(wherein X is C₁-C₄ alkyl). Pharmaceutically acceptable salts of anitrogen atom or an amino group include for example salts of organiccarboxylic acids such as acetic, benzoic, camphorsulfonic, citric,glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic,malic, mandelic, isethionic, lactobionic, succinic,2-napththalenesulfonic, oleic, palmitic, propionic, stearic, andtrimethylacetic acids; organic sulfonic acids, such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; andinorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group). Pharmaceuticallyacceptable salts also include salts formed when an acidic proton presentin the parent compound is replaced by either a metal ion, e.g., analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as diethanolamine,triethanolamine, N-methylglucamine and the like. Also included in thisdefinition are ammonium and substituted or quaternized ammonium salts.Representative non-limiting lists of pharmaceutically acceptable saltscan be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977),and Remington: The Science and Practice of Pharmacy, R. Hendrickson,ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.,(2005), at p. 732, Table 38-5, both of which are hereby incorporated byreference herein.

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of formula I or another compound disclosedherein. All salts, whether or not derived from a physiologicallyacceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound disclosed herein. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, such as amines. Finally, it is to be understoodthat the compositions herein comprise compounds disclosed herein intheir un-ionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

Isotopes

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,in certain embodiments, a —CH₃ group is replaced with —CD₃.

Specific values listed below for radicals, substituents, and ranges inthe embodiments of the invention are for illustration only; they do notexclude other defined values or other values within defined ranges forthe radicals and substituents.

Compounds of Formula I.

A specific group of compounds of formula I are compounds of formula Ia.

or a pharmaceutically acceptable salt thereof.

Another specific group of compounds of formula I are compounds offormula Ib.

or a pharmaceutically acceptable thereof.

Another specific group of compounds of formula I are compounds offormula Ic.

or a pharmaceutically acceptable thereof.

Another specific group of compounds of formula I are compounds offormula Id.

or a pharmaceutically acceptable thereof.

Another specific group of compounds of formula I are compounds offormula Ie.

or a pharmaceutically acceptable thereof.

Another specific group of compounds of formula I are compounds offormula If.

or a pharmaceutically acceptable thereof.

Another specific group of compounds of formula I are compounds offormula Ig.

or a pharmaceutically acceptable thereof.

Specific values listed below are values for compounds of formula I aswell as all related formulas (e.g., formulas Ia, Ib, Ic, Id, Ie, If,Ig). It is to be understood that two or more values may combined. Thus,it is to be understood that any variable for compounds of formula I maybe combined with any other variable for compounds of formula I the sameas if each and every combination of variables were specifically andindividually listed. For example, it is understood that any specificvalue of R¹ detailed herein for compounds of formula I may be combinedwith any other specific value for one or more of the variables A, Z¹,R², R^(3a) or R^(3b) the same as if each and every combination werespecifically and individually listed.

Specific values listed for compounds of formula I may apply equally tocompounds of formula III and all related formulas (e.g., formulas IIIa,IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk) asapplicable. For example, specific values for ring A of formula I mayapply equally to ring A of formula III provided that the ring A offormula III encompasses within its scope the specific values. It is alsounderstood that any combination of variables for compounds of formula Imay apply equally to compounds of formula III and all related formulas(e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi,IIIj, and IIIk) as applicable, the same as if each and every combinationwere specifically and individually listed. For example, specific valuesfor ring A and Z¹ may apply equally to the A-Z¹ moeity of formula IIIprovided that the scope of the A-Z¹ moiety of formula III encompassesthe specific value.

A specific group of compounds of formula I are compounds wherein eachR^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl, and (C₁-C₃)haloalkyl.

A specific group of compounds of formula I are compounds wherein eachR^(3a) and R^(3b) is independently selected from H, (C₁-C₃)alkyl, and(C₁-C₃)haloalkyl.

A specific group of compounds of formula I are compounds wherein eachR^(3a) and R^(3b) is independently selected from H and (C₁-C₃)alkyl.

A specific group of compounds of formula I are compounds wherein eachR^(3a) and R^(3b) is independently selected from H, methyl and ethyl.

A specific group of compounds of formula I are compounds wherein eachR^(3a) and R^(3b) is independently selected from H and methyl.

A specific group of compounds of formula I are compounds wherein R^(3a)is H and R^(3b) is (C₁-C₃)alkyl.

A specific group of compounds of formula I are compounds wherein R^(3a)is H and R^(3b) is methyl or ethyl.

A specific group of compounds of formula I are compounds wherein R^(3a)is H and R^(3b) is methyl.

A specific value for R^(3a) and R^(3b) is H.

A specific value for R² is phenyl or a 5-membered monocyclic-heteroaryl,wherein any phenyl or 5-membered monocyclic-heteroaryl of R² isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁵groups.

A specific value for R² is phenyl or a 5-membered monocyclic-heteroaryl,wherein any phenyl or 5-membered monocyclic-heteroaryl of R² issubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁵ groups.

A specific value for R² is phenyl optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁵ groups.

A specific value for R² is phenyl substituted with one or more (e.g., 1,2, 3, 4 or 5) Z⁵ groups.

A specific value for Z⁵ is halogen.

A specific value for Z⁵ is fluoro.

A specific value for R² is 3,5-difluorophenyl.

A specific value for A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl of A is substituted with one Z¹ group at the position shown,one Z² group and optionally substituted with one or more (e.g., 1 or 2)Z³ groups.

A specific value for A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl of A is substituted with one Z¹ group at the position shownand one Z² group.

A specific value for A is pyridinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown, one Z² group, andoptionally substituted with one or more (e.g., 1 or 2) Z³ groups.

A specific value for A is pyridinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown and one Z² group

A specific value for A is selected from:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for A is selected from:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for A is selected from:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for A is:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for A is:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for A is:

wherein each Z^(3a) is independently selected from H and Z³.

A specific value for Z^(3a) is H.

A specific value for Z¹ is selected from phenyl, 5-14 memberedheteroaryl and 3-14 membered heterocycle, wherein any phenyl, 5-14membered heteroaryl and 3-14 membered heterocycle of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups.

A specific value for Z¹ is selected from phenyl, 5-12 memberedheteroaryl and 3-12 membered heterocycle, wherein any phenyl, 5-12membered heteroaryl and 3-12 membered heterocycle of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups.

A specific value for Z¹ is selected from phenyl, 5-14 memberedheteroaryl and 3-14 membered heterocycle, wherein any phenyl, 5-14membered heteroaryl and 3-14 membered heterocycle of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is selected from phenyl, 5-12 memberedheteroaryl and 3-12 membered heterocycle, wherein any phenyl, 5-12membered heteroaryl and 3-12 membered heterocycle of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle have 1-11 carbon atoms and 1-5heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a)or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle have 1-11 carbon atoms and 1-5heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a)groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle have 4-11 carbon atoms and 1-3heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a)or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle have 4-11 carbon atoms and 1-3heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a)groups.

A specific value for Z¹ is selected from 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle, wherein anyfrom 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle, wherein anyfrom 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) groups.

A specific value for Z¹ is selected from 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle, wherein the8-10 membered bicyclic-heteroaryl and 8-10 membered bicyclic-heterocyclehave 3-9 carbon atoms and 1-5 heteroatoms in the ring system, andwherein any 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle, wherein the8-10 membered bicyclic-heteroaryl and 8-10 membered bicyclic-heterocyclehave 3-9 carbon atoms and 1-5 heteroatoms in the ring system, andwherein any 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups. A specific value for Z¹ is 1H-indazol-7-yl, wherein Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl as shown by the followingformulas;

wherein any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups. A specific value for Z¹ is

A specific value for Z¹ is

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, pyridinyl and quinazolinyl,wherein any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, pyridinyl and quinazolinylof Z¹ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, pyridinyl and quinazolinyl,wherein any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, pyridinyl and quinazolinylof Z¹ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(1a) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl,pyridin-4-yl and quinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl,pyridin-4-yl and quinazolin-8-yl of Z¹ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl as shown by thefollowing formulas;

wherein any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b)groups. A specific value for Z¹ is

A specific value for Z¹ is

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl of Z¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific value for Z¹ is selected from phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl,pyridin-4-yl and quinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl,pyridin-4-yl and quinazolin-8-yl of Z¹ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) groups.

A specific group of compounds of formula I are compounds wherein Z¹ isnot substituted with Z^(1b).

A specific value for each Z^(1a) is independently selected from halogen,—OR^(n1) and —C(O)NR^(q1)R^(r1).

A specific value for each Z^(1a) is independently selected from halogenand —C(O)NR^(q1)R^(r1).

A specific value for each R^(n1), R^(q1) and R^(r1) are each H.

A specific value for each Z^(1a) is independently selected from halogen,—OH and —C(O)NH₂.

A specific value for each Z^(1a) is independently selected from fluoro,—OH and —C(O)NH₂.

A specific value for R_(q1) and R^(r1) is H.

A specific value for each Z^(1a) is independently selected from halogenand —NR^(n1)S(O)₂R^(p1).

A specific value for each Z^(1b) is (C₁-C₈)alkyl, which may be same ordifferent.

In certain embodiments, each Z^(1a) is independently selected fromhalogen and NR^(n1)S(O)₂R^(p1) and each Z^(1b) is (C₁-C₈)alkyl, whichmay be same or different.

A specific value for Z¹ is selected from:

A specific value for Z¹ is

A specific value for Z¹ is

A specific value for Z² is selected from (C₂-C₈)alkynyl, 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle and —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl and 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from (C₂-C₈)alkynyl, 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle and —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl and 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(2c) groups, and wherein any (C₂-C₈)alkynyl ofZ² is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(2c) groups.

A specific value for Z² is selected from (C₂-C₈)alkynyl, phenyl, 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from (C₂-C₈)alkynyl, phenyl, 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(2c) groups, and wherein any(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from (C₂-C₈)alkynyl, phenyl, 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered andC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from (C₂-C₈)alkynyl, phenyl, 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered andC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more (e.g., 1, 2, 3, 4 or 5) Z^(2c) groups, and wherein any(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from 4-methylpentynyl, phenyl,pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl,1H-pyrrolo[2,3-b]pyridinyl and —C(O)NR^(q3)R^(r3), wherein any phenyl,pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl and1H-pyrrolo[2,3-b]pyridinyl of Z² is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any4-methylpentynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from 4-methylpentynyl, phenyl,pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl,1H-pyrrolo[2,3-b]pyridinyl and —C(O)NR^(q3)R^(r3), wherein any phenyl,pyridinyl, 2-oxopyridinyl, triazolyl, 1-oxoisoindolinyl and1H-pyrrolo[2,3-b]pyridinyl of Z² is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(2c) groups, and wherein any4-methylpentynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4 or 5) Z^(2c) groups.

A specific value for Z² is selected from 4-methylpentyn-1-yl, phenyl,pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl,1H-pyrrolo[2,3-b]pyridine-5-yl and —C(O)NR^(q3)R^(r3), wherein anyphenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl,1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridine-5-yl of Z² isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b)or Z^(2c) groups, and wherein any 4-methylpentyn-1-yl of Z² isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2c)groups.

A specific value for Z² is selected from 4-methylpentyn-1-yl, phenyl,pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl,1H-pyrrolo[2,3-b]pyridine-5-yl and —C(O)NR^(q3)R^(r3), wherein anyphenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl,1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridine-5-yl of Z² isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2c)groups, and wherein any 4-methylpentyn-1-yl of Z² is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2c) groups.

A specific group of compounds of formula I are compounds wherein each Z²is not substituted with Z^(2b).

A specific group of compounds of formula I are compounds wherein each Z²is optionally substituted with one or more Z^(2c) groups.

A specific value for each Z^(2c) is independently selected from halogen,—OR_(n4) and —C(O)NR_(q4)R_(r4).

A specific group of compounds of formula I are compounds wherein R^(n4)is H or methyl, and R^(q4) and R^(r4) are each H.

A specific value for R^(n4) is H or methyl.

A specific value for each R^(q4) and R^(r4) is H.

A specific value for Z² is selected from:

A specific value for A-Z¹ is selected from:

A specific value for A-Z¹ is selected from:

A specific value for R¹ is a 5-12 membered heteroaryl, wherein any 5-12membered heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4, or 5) Z⁴ groups.

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) Z⁴groups.

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl have 4-10carbon atoms and 1-5 heteroatoms in the ring system, and wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with one or more (e.g., 1, 2, 3, 4, or5) Z⁴ groups.

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl contains atleast one partially unsaturated ring, and wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴groups.

A specific value for R¹ has the following formula IIa:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-8 memberedbicyclic heterocycle, wherein any 3-7 membered monocyclic-carbocycle,5-8 membered bicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or5-8 membered bicyclic heterocycle of C is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

B is a 5 or 6 membered monocyclic-heteroaryl with 1, 2 or 3 nitrogenatoms, wherein B is optionally substituted with one or more or (e.g. 1,2, 3, 4 or 5) Z⁴ groups.

A specific value for R¹ has the following IIb:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-8 memberedbicyclic heterocycle, wherein any 3-7 membered monocyclic-carbocycle,5-8 membered bicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or5-8 membered bicyclic heterocycle of C is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c), NZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴.

A specific value for R¹ has the following formula IIc:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-8 memberedbicyclic heterocycle, wherein any 3-7 membered monocyclic-carbocycle,5-8 membered bicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or5-8 membered bicyclic heterocycle of C is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴.

A specific value for R¹ has the following R¹ has the following formulaIId:

wherein:

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle, 5-9 membered bicyclic-carbocycle, 3-7membered monocyclic-heterocycle or 5-9 membered bicyclic heterocycle,wherein any 3-7 membered monocyclic-carbocycle, 5-9 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-9 memberedbicyclic heterocycle of C is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

each Z^(4c) is independently selected from H or Z⁴.

A specific value for each Z⁴ is independently selected from (C₁-C₆)alkyland halogen, wherein any (C₁-C₆)alkyl of Z⁴ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4, or 5) halogen.

A specific value for each Z⁴ is independently selected from fluoro,trifluoromethyl and difluoromethyl.

A specific value for R¹ is selected from:

A specific value for R¹ is selected from:

A specific value for R¹ is

A specific value for R¹ is

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl has 4-9 carbonatoms and 1-5 heteroatoms in the ring system, and wherein any 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴groups.

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl, whereinthe 8-12 membered bicyclic-heteroaryl has 6-9 carbon atoms and 1-3heteroatoms in the ring system, and wherein any 8-12 memberedbicyclic-heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl has 6-9 carbonatoms and 1-3 heteroatoms in the ring system, and wherein any 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴groups.

A specific value for R¹ is selected from indolyl and4,5,6,7-tetrahydro-indazolyl, wherein any indolyl and4,5,6,7-tetrahydro-indazolyl of R¹ optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for R¹ is selected from indolyl,4,5,6,7-tetrahydro-indazolyl,3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole, wherein any indolyl,4,5,6,7-tetrahydro-indazolyl,3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole of R¹ is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for R¹ is selected from indol-3-yl and4,5,6,7-tetrahydro-1H-indazol-1-yl, wherein any indol-3-yl and4,5,6,7-tetrahydro-1H-indazol-1-yl of R¹ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for R¹ is selected from indol-3-yl,4,5,6,7-tetrahydro-1H-indazol-1-yl,3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl, wherein anyindol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-1-yl,3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl of R¹ optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

A specific value for each Z⁴ is independently selected from (C₁-C₆)alkyland halogen, wherein any (C₁-C₆)alkyl of Z⁴ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) halogen.

A specific value for each Z⁴ is independently selected from(C₁-C₆)alkyl, —CN and halogen, wherein any (C₁-C₆)alkyl of Z⁴ isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) halogen.

A specific value for each Z⁴ is independently selected from fluoro,trifluoromethyl and difluoromethyl.

A specific value for each Z⁴ is independently selected from fluoro,trifluoromethyl, —CN and difluoromethyl.

A specific value for R¹ is selected from:

A specific value for R¹ is selected from:

A specific value for R¹ is selected from:

A specific value for R¹ is

A specific value for R¹ is

In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl; and R¹ is a 5-12 membered heteroaryl, optionallysubstituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be the same ordifferent. In another variation, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups. In anothervariation, A is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; R¹ isa 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl, wherein any 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl of R¹ is optionally substituted with1, 2, 3, 4, or 5 Z⁴ groups; and each Z⁴ is independently fluoro,trifluoromethyl, or difluoromethyl.

In one variation of formula I, A is pyridinyl; and R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl, wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups.

In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyridinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyrimidinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyrazinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyridazinyl; and R² is 3,5-difluorophenyl.

In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl; and Z¹ is phenyl, 5-6 membered monocyclic-heteroaryl, 8-10membered bicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or9-12 membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In anothervariation, A is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; and Z¹is phenyl, optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. Inanother variation, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl; and Z¹ is 5-6 membered monocyclic-heteroaryl or 8-10membered bicyclic-heteroaryl, wherein any 5-6 memberedmonocyclic-heteroaryl or 8-10 membered bicyclic-heteroaryl of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In anothervariation, A is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; and Z¹is 8-10 membered bicyclic-heterocycle or 9-12 memberedtricyclic-heterocycle wherein any 8-10 membered bicyclic-heterocycle or9-12 membered tricyclic-heterocycle of Z¹ is optionally substituted with1, 2, 3, 4 or 5 Z^(1a) groups.

In one variation of formula I, A is pyridinyl; and Z¹ is phenyl, 5-6membered monocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10membered bicyclic-heterocycle, or 9-12 membered tricyclic-heterocyclewherein any phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups. In another variation, A is pyridinyl; and Z¹is phenyl, optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. Inanother variation, A is pyridinyl; and Z¹ is 5-6 memberedmonocyclic-heteroaryl or 8-10 membered bicyclic-heteroaryl, wherein any5-6 membered monocyclic-heteroaryl or 8-10 membered bicyclic-heteroarylof Z¹ is optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. Inanother variation, A is pyridinyl; and Z¹ is 8-10 memberedbicyclic-heterocycle or 9-12 membered tricyclic-heterocycle wherein any8-10 membered bicyclic-heterocycle or 9-12 memberedtricyclic-heterocycle of Z¹ is optionally substituted with 1, 2, 3, 4 or5 Z^(1a) groups.

In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups. In another variation, A is pyridinyl; and Z² is(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups. In anothervariation, A is pyrimidinyl; and Z² is (C₂-C₈)alkynyl, 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups. In anothervariation, A is pyrazinyl; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,or —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups. In another variation, A is pyridazinyl; and Z² is(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In one variation of formula I, A is pyridinyl substituted with one Z¹moiety, one Z² moiety and no (zero) Z³ moieties; and Z² is(C₂-C₈)alkynyl or aryl, which Z² may be optionally substituted asprovided by formula I. In another variation, A is pyridinyl substitutedwith one Z¹ moiety, one Z² moiety and no (zero) Z³ moieties; and Z² is(C₂-C₈)alkynyl, which Z² may be optionally substituted as provided byformula I. In a particular variation, A is pyridinyl substituted withone Z¹ moiety, one Z² moiety at the position alpha to the nitrogen atomof the pyridinyl ring, and no (zero) Z³ moieties, wherein Z² is(C₂-C₈)alkynyl, which Z² may be optionally substituted as provided byformula I.

In one variation of formula I, R¹ is a 5-12 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be thesame or different; and Z¹ is phenyl, 5-6 membered monocyclic-heteroaryl,8-10 membered bicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle,or 9-12 membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In anothervariation, R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl, wherein any 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl of R¹ is optionally substituted with1, 2, 3, 4, or 5 Z⁴ groups; and Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups.

In one variation of formula I, R¹ is a 8-12 membered bicyclic-heteroarylor 8-12 membered tricyclic-heteroaryl, wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups; and Z¹ is 8-10membered bicyclic-heteroaryl or 8-10 membered bicyclic-heterocyclewherein any 8-10 membered bicyclic-heteroaryl or 8-10 memberedbicyclic-heterocycle of Z¹ is optionally substituted with 1, 2, 3, 4 or5 Z^(1a) groups.

In one variation of formula I, R¹ is a 5-12 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be thesame or different; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups. In another variation, R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups; and Z²is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) group.

In one variation of formula I, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups; and Z² is (C₂-C₈)alkynyl, 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In one variation of formula I, Z¹ is bicyclic-heteroaryl optionallysubstituted with 1, 2, 3, 4 or 5 Z^(1a) groups; and Z² is (C₂-C₈)alkynyloptionally substituted with 1, 2, 3, 4 or 5 Z^(2C) groups.

In one variation of formula I, R¹ is a 5-12 membered heteroaryl; Z¹ isphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups; and Z² is(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

Compounds of Formula III.

The present disclosure provides compounds of formula III:

wherein

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 or 2 Z³ groups, wherein the Z³ groups are the same or different;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different;

R² is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogen, whichare the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are thesame or different;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂N^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl, or(C₁-C₄)haloalkyl;

each Z^(2c) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl or halogen;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6); and

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula III is a compound offormula IIIa.

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula III is a compound offormula IIIb.

or a pharmaceutically acceptable thereof.

In certain embodiments, a compound of formula III is a compound offormula IIIc.

or a pharmaceutically acceptable thereof.

The present disclosure provides compounds of formula IIId:

wherein

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are thesame or different;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2C) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6);

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

each Z⁵ is independently halogen, which may be same or different; and

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula IIId is a compound offormula IIIe.

or a pharmaceutically acceptable salt thereof.

The present disclosure provides compounds of formula IIIf:

wherein

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are thesame or different;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), C(O)R^(n1),C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2C) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6);

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

each Z⁵ is independently halogen, which may be same or different; and

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula IIIf is a compound offormula IIIg.

or a pharmaceutically acceptable salt thereof.

The present disclosure provides compounds of formula IIIh:

wherein

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle or 5-9 membered bicyclic-carbocycle,wherein any 3-7 membered monocyclic-carbocycle or 5-9 memberedbicyclic-carbocycle of C is optionally substituted with 1, 2, 3, 4 or 5Z⁴ groups, wherein the Z⁴ groups are the same or different;

each Z^(1w) is independently Z^(1a), Z^(1b) or H;

each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different;

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which are the same or different;

each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl;

each Z^(1d) is independently (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;

each R^(n1) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(n1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl of R^(q1) or R^(r1)is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(q1) or R^(r1) is optionally substitutedwith 1, 2, 3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are thesame or different, or R^(q1) and R^(r1) together with the nitrogen towhich they are attached form a 5, 6 or 7-membered heterocycle, whereinthe 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groupsare the same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,wherein the Z^(2b) and Z^(2c) groups are the same or different, andwherein any (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of Z² is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups, wherein the Z^(2c)groups are the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2c) is independently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)heteroalkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;

Z³ is independently a (C₁-C₄)heteroalkyl;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, wherein the Z^(4a) groups are the same ordifferent;

each Z^(4a) is independently halogen, —CN, or —OR^(n6);

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl; and

Z^(5a) is H or halogen;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula IIIb is a compound offormula IIIi.

or a pharmaceutically acceptable salt thereof.

The present disclosure provides compounds of formula IIIj:

wherein

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

Z^(1x) is H or (C₁-C₈)alkyl;

Z^(1y) is —NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1),—NR^(q1)R^(r1), —NR^(n1)COR^(p1), —NR^(n1)CONR^(q1)R^(r1), or—NR^(n1)CO₂R^(p1);

Z^(1z) is H, halogen, —CN, —OR^(n1), (C₁-C₈)alkyl, wherein the(C₁-C₈)alkyl is optionally substituted with 1, 2, or 3 halogen, whichare the same or different;

each R^(n1) is independently H or (C₁-C₈)alkyl;

each R^(p1) is independently (C₁-C₈)alkyl;

each R^(q1) and R^(r1) is independently H or (C₁-C₈)alkyl;

Z³ is (C₁-C₄)heteroalkyl;

Z² is (C₂-C₈)alkynyl, optionally substituted with 1, 2, 3, 4, or 5Z^(2c) group, wherein the Z^(2c) groups are the same or different;wherein Z^(2c) is independently halogen, —OR^(n4), —NR^(n4)CO₂R^(p4),—C(O)OR^(n4), or —NR^(q4)R^(r4);

each R^(n4) is independently H or (C₁-C₄)alkyl;

each R^(p4) is independently (C₁-C₄)alkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl, or(C₁-C₄)heteroalkyl;

Z⁴ is hydrogen, (C₁-C₈)alkyl, halogen, —CN, C(O)R^(n5), —C(O)OR^(n5),—C(O)NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(q5)R^(r5), or(C₃-C₇)carbocycle, wherein any (C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴is optionally substituted with halogen or hydroxyl;

each R^(n5) is independently H or (C₁-C₄)alkyl;

each R^(p5) is independently H or (C₁-C₄)alkyl;

each R^(q5) and R^(r5) is independently H or (C₁-C₄)alkyl; and

Z^(5a) is H or halogen;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula IIIj is a compound offormula IIIk

or a pharmaceutically acceptable salt thereof.

Specific values listed below are values for compounds of formula III aswell as all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId,IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk) where applicable. Forexample, values recited below as applying to formula III apply equallyto all related formulas of formula III (e.g., formulas IIIa, IIIb, IIIc,IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk) that permit thepresence of such variable. It is to be understood that two or morevalues may combined. Thus, it is to be understood that any variable forcompounds of formula III may be combined with any other variable forcompounds of formula III the same as if each and every combination ofvariables were specifically and individually listed. For example, it isunderstood that any specific value of R¹ detailed herein for compoundsof formula III may be combined with any other specific value for one ormore of the variables A, Z¹, R², R^(1a) or R^(3b) of formula III thesame as if each and every combination were specifically and individuallylisted.

In certain embodiments of formula III, A¹ is CH. In certain embodiments,A¹ is C—Z³. In certain embodiments, A¹ is nitrogen.

In certain embodiments of formula III, A² is CH. In certain embodiments,A² is nitrogen.

In certain embodiments of formula III, A¹ is CH; and A² is CH. Incertain embodiments, A¹ is C—Z³; and A² is CH. In certain embodiments,A¹ is nitrogen; and A² is CH.

In certain embodiments of formula III, A¹ is CH; and A² is nitrogen. Incertain embodiments, A¹ is C—Z³; and A² is nitrogen. In certainembodiments, A¹ is nitrogen; and A² is nitrogen.

In certain embodiments of formula III, Z⁵ is F. In certain embodimentsof formula III, n is one. In certain embodiments, n is two. In certainembodiments of formula III, n is one and Z⁵ is F. In certainembodiments, n is two and each Z⁵ is F.

In certain embodiments of formula III, Z^(5a) is H. In certainembodiments, Z^(5a) is F.

In certain embodiments of formula III, each Z^(1w) is independentlyZ^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups may be the sameor different. In certain embodiments, each Z^(1w) is independently(C₁-C₈)alkyl, halogen, or —NR^(n1)S(O)₂R^(p1), which may be same ordifferent.

In certain embodiments of formula III, Z^(1x) is H. In certainembodiments, Z^(1x) is (C₁-C₈)alkyl. In certain embodiments, Z^(1x) is(C₁-C₄)alkyl. In certain embodiments, Z^(1x) is (C₁-C₃)alkyl. In certainembodiments, Z^(1x) is methyl.

In certain embodiments of formula III, Z^(1y) is —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂NR^(q1)R^(r1), or —NR^(q1)R^(r1). In certain embodiments,Z^(1y) is —NR^(n1)S(O)₂R^(p1)or —NR^(n1)S(O)₂NR^(q1)R^(r1). In certainembodiments, Z^(1y) is —NR^(n1)S(O)₂R^(p1). In certain embodiments,Z^(1y) is —NR^(n1)S(O)₂N^(q1)R^(r1). In certain embodiments, Z^(1y) is—N^(q1)R^(r1).

In certain embodiments of formula III, Z^(1z) is H or halogen. Incertain embodiments, Z^(1z) is H. In certain embodiments, Z^(1z) ishalogen. In certain embodiments, Z^(1z) is Cl. In certain embodiments,Z^(1z) is F. In certain embodiments, Z^(1z) is Br.

In certain embodiments of formula III, Z^(1y) is —NR^(n1)S(O)₂R^(p1) or—NR^(n1)S(O)₂NR^(n1)R^(r1) and Z^(1z) is halogen. In certainembodiments, Z^(1y) is —NR^(n1)S(O)₂R^(p1) and Z^(1z) is halogen. Incertain embodiments, Z^(1x) is (C₁-C₄)alkyl; Z^(1y) is—NR^(n1)S(O)₂R^(p1) or —NR^(n1)S(O)₂NR^(q1)R^(r1); and Z^(1z) ishalogen. In certain embodiments, Z^(1x) is (C₁-C₄)alkyl; Z^(1y) is—NR^(n1)S(O)₂R^(p1); and Z^(1z) is halogen.

In certain embodiments of formula III, A is pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl of A is substituted with one Z¹ group at the positionshown, one Z² group and optionally substituted with 1 or 2 Z³ groups. Incertain embodiments, A is pyridinyl, pyrimidinyl, pyrazinyl, orpyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl of A is substituted with one Z¹ group at the position shown,one Z² group and optionally substituted with 1 Z³ group.

In certain embodiments, A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl of A is substituted with one Z¹ group at the position shownand one Z² group. In one aspect, A is not substituted with a Z³ group.

In certain embodiments, A is pyridinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown, one Z² group, andoptionally substituted with 1 or 2 Z³ groups. In certain embodiments, Ais pyridinyl, wherein any pyridinyl of A is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 Z³ group.

In certain embodiments, A is pyridinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown and one Z² group. Inone aspect, the Z² group attached at the position alpha to the nitrogenof the pyridinyl group. In a further aspect, A is not substituted with aZ³ group.

In certain embodiments, A is pyrimidinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown, one Z² group, andoptionally substituted with 1 or 2 Z³ groups. In certain embodiments, Ais pyrimidinyl, wherein any pyridinyl of A is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 Z³ group.

In certain embodiments, A is pyrimidinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown and one Z² group. Inone aspect, A is not substituted with a Z³ group.

In certain embodiments, A is pyrazinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown, one Z² group, andoptionally substituted with 1 or 2 Z³ groups. In certain embodiments, Ais pyrazinyl, wherein any pyridinyl of A is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 Z³ group.

In certain embodiments, A is pyrazinyl, wherein any pyridinyl of A issubstituted with one Z¹ group at the position shown and one Z² group. Inone aspect, A is not substituted with a Z³ group.

In certain embodiments, A is:

In certain embodiments, A is:

In certain embodiments, A is:

In certain embodiments, A is:

In certain embodiments, A is:

In certain embodiments of formula III, R² is phenyl optionallysubstituted with 1, 2, or 3 halogens, which may be the same ordifferent. In certain embodiments, R² is phenyl optionally substitutedwith 1 or 2 halogens, which may be the same or different. In certainembodiments, R² is phenyl optionally substituted with 2 halogens, whichmay be the same or different. In certain embodiments, R² is phenyloptionally substituted with 1 halogen.

In certain embodiments, R² is 3,5-difluorophenyl or 3-fluorophenyl. Incertain embodiments, R² is 3,5-difluorophenyl. In certain embodiments,R² is 3-fluorophenyl.

In certain embodiments, the moiety

wherein Z^(5a) is H or halogen.

In certain embodiments of formula III, each Z³, where present, isindependently methoxy, dimethylamino, or methylamino. In certainembodiments, Z³, where present, is methoxy. In certain embodiments, Z³,where present, is dimethylamino. In certain embodiments, Z³, wherepresent, is methylamino. In certain embodiments, Z³, where present, ishalogen. In certain embodiments, Z³, where present, is fluoro. Incertain embodiments, Z³, where present, is chloro. In certainembodiments, Z³, where present, is bromo.

In certain embodiments of formula III, each R^(3a) and R^(3b) are eachH. In certain embodiments, R^(3a) is methyl and R^(3b) is H.

In certain embodiments of formula III, Z² is (C₂-C₈)alkynyl, 6-12membered aryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In certain embodiments, Z² is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups, and whereinany (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3, 4 or 5Z^(2c) groups.

In certain embodiments, Z² is (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle, or —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, or 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with 1, 2,3, 4 or 5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z²is optionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In certain embodiments, Z² is (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle, or —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, or 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with 1, 2,3, 4 or 5 Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In certain embodiments, Z² is (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle, or —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, or 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered andC-linked-bicyclic-heterocycle of Z² is optionally substituted with 1, 2,3, 4 or 5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z²is optionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In certain embodiments, Z² is (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle, or —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, or 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered, orC-linked-bicyclic-heterocycle of Z² is optionally substituted with 1, 2,3, 4 or 5 Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In certain embodiments of formula III, Z² is (C₂-C₈)alkynyl, optionallysubstituted with 1, 2, 3, 4, or 5 Z^(2c) groups. In certain embodiments,Z² is (C₂-C₈)alkynyl, optionally substituted with 1, 2, 3, or 4 Z^(2c)groups. In certain embodiments, Z² is (C₂-C₈)alkynyl, optionallysubstituted with 1, 2, or 3 Z^(2c) groups. In certain embodiments, Z² is(C₂-C₈)alkynyl, optionally substituted with 1 or 2 Z^(2c) groups.

In certain embodiments, Z² is of the formula:

wherein each of the (C₁-C₄)alkyl moieties of Z², if present, isoptionally substituted with 1, 2 or 3 Z^(2c) groups, wherein the Z^(2b)groups may be the same or different.

In certain embodiments, Z² is of the formula:

wherein each of the (C₁-C₄)alkyl moieties of Z² is optionallysubstituted with 1, 2 or 3 Z^(2c) groups, wherein the Z^(2b) groups maybe the same or different.

In certain embodiments, Z² is of the formula:

wherein each of the (C₁-C₄)alkyl moieties of Z² is optionallysubstituted with 1, 2 or 3 Z^(2c) groups, wherein the Z^(2b) groups maybe the same or different.

In certain embodiments of formula III, Z² is substituted with 1, 2, 3,or 4 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c) groups maybe the same or different. In certain embodiments, Z² is substituted with1, 2, or 3 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c) groupsmay be the same or different. In certain embodiments, Z² is substitutedwith 1 or 2 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c)groups may be the same or different. In certain embodiments, Z² issubstituted with 1 Z^(2b) or Z^(2c) group.

In certain embodiments of formula III, Z² is optionally substituted with1, 2, or 3 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c) groupsmay be the same or different. In certain embodiments, Z² is substitutedwith 1 Z^(2b) or Z^(2c) group. In certain embodiments, Z² is substitutedwith 2 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c) groups maybe the same or different. In certain embodiments, Z² is substituted with3 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c) groups may bethe same or different.

In certain embodiments of formula III, Z² is substituted with 1, 2, 3,or 4 Z^(2c) groups, wherein the Z^(2c) groups may be the same ordifferent. In certain embodiments, Z² is substituted with 1, 2, or 3Z^(2c) groups, wherein the Z^(2c) groups may be the same or different.In certain embodiments, Z² is substituted with 1 or 2 Z^(2c) groups,wherein the Z^(2c) groups may be the same or different. In certainembodiments, Z² is substituted with 1 Z^(2c) group.

In certain embodiments of formula III, Z² is optionally substituted with1, 2, or 3 Z^(2c) groups, wherein the Z^(2c) groups may be the same ordifferent. In certain embodiments, Z² is substituted with 1 Z^(2c)group. In certain embodiments, Z² is substituted with 2 Z^(2c) groups,wherein the Z^(2c) groups may be the same or different. In certainembodiments, Z² is substituted with 3 Z^(2c) groups, wherein the Z^(2c)groups may be the same or different.

In certain embodiments, each Z^(2c) is independently halogen, —OR^(n4),NR^(q4)R^(r4), —NR^(n4)CO₂R^(p4), —C(O)OR^(n4), or —C(O)NR^(q4)R^(r4).In certain embodiments, each Z^(2c) is independently halogen or—OR^(n4).

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is —C(O)NH₂,

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is

—C(O)NH₂.

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is

In certain embodiments, Z² optionally substituted with 1, 2, 3, 4, or 5Z^(2b) or Z^(2c) groups is

In certain embodiments of formula III, R¹ is a 5-12 membered heteroaryl,wherein any 5-12 membered heteroaryl of R¹ is optionally substitutedwith 1, 2, 3, 4, or 5 Z⁴ groups.

In certain embodiments of formula III, R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl, wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered tricyclic-heteroaryl of R¹ is optionallysubstituted with 1, 2, 3, 4, or 5 Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl have 4-10carbon atoms and 1-5 heteroatoms in the ring system, and wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl contains atleast one partially unsaturated ring, and wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered tricyclic-heteroaryl contains at least onepartially unsaturated ring, and wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups.

In certain embodiments of formula III, R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl, wherein the8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylhas 4-9 carbon atoms and 1-5 heteroatoms in the ring system, and whereinany 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with 1, 2, 3, 4 or5 Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered bicyclic-heteroaryl,wherein the 8-12 membered bicyclic-heteroaryl has 6-9 carbon atoms and1-3 heteroatoms in the ring system, and wherein any 8-12 memberedbicyclic-heteroaryl of R¹ is optionally substituted with 1, 2, 3, 4 or 5Z⁴ groups.

In certain embodiments, R¹ is a 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl, wherein the 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl has 6-9 carbonatoms and 1-3 heteroatoms in the ring system, and wherein any 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹is optionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups.

In certain embodiments of formula III, R¹ has the following formula IIa:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle, or 5-8membered bicyclic heterocycle, wherein any 3-7 memberedmonocyclic-carbocycle, 5-8 membered bicyclic-carbocycle, 3-7 memberedmonocyclic-heterocycle or 5-8 membered bicyclic heterocycle of C isoptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, wherein the Z⁴groups are the same or different; and

B is a 5 or 6 membered monocyclic-heteroaryl with 1, 2 or 3 nitrogenatoms, wherein B is optionally substituted with 1, 2, 3, 4 or 5 Z⁴groups, wherein the Z⁴ groups are the same or different.

In certain embodiments of formula III, R¹ has the following formula IIb:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle, or 5-8membered bicyclic heterocycle, wherein any 3-7 memberedmonocyclic-carbocycle, 5-8 membered bicyclic-carbocycle, 3-7 memberedmonocyclic-heterocycle or 5-8 membered bicyclic heterocycle of C isoptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, wherein the Z⁴groups are the same or different; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c), NZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴, wherein the Z⁴groups are the same or different.

In certain embodiments of formula III, R¹ has the following formula IIc:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle, or 5-8membered bicyclic heterocycle, wherein any 3-7 memberedmonocyclic-carbocycle, 5-8 membered bicyclic-carbocycle, 3-7 memberedmonocyclic-heterocycle or 5-8 membered bicyclic heterocycle of C isoptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, wherein the Z⁴groups are the same or different; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴, wherein the Z⁴groups are the same or different.

In certain embodiments of formula III, R¹ has the following formula IId:

wherein:

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle, 5-9 membered bicyclic-carbocycle, 3-7membered monocyclic-heterocycle, or 5-9 membered bicyclic heterocycle,wherein any 3-7 membered monocyclic-carbocycle, 5-9 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-9 memberedbicyclic heterocycle of C is optionally substituted with 1, 2, 3, 4 or 5Z⁴ groups, wherein the Z⁴ groups are the same or different; and

each Z^(4c) is independently selected from H or Z⁴, wherein the Z⁴groups are the same or different.

In certain embodiments of formula III, R¹ has the following formula:

wherein:

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle or 5-9 membered bicyclic-carbocycle,wherein any 3-7 membered monocyclic-carbocycle or 5-9 memberedbicyclic-carbocycle of C is optionally substituted with 1, 2, 3, 4 or 5Z⁴ groups, wherein the Z⁴ groups are the same or different.

In certain embodiments of formula III, R¹ has the following formula:

In certain embodiments of formula III, C together with the two carbonatoms to which it is attached forms a 5-7 membered monocyclic-carbocycleor 5-7 membered bicyclic-carbocycle, wherein any 5-7 memberedmonocyclic-carbocycle or 5-7 membered bicyclic-carbocycle of C isoptionally substituted with 1, 2, 3, or 4 Z⁴ groups, wherein the Z⁴groups are the same or different.

In certain embodiments of formula III, each Z⁴ is independently(C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen, —CN, —NR^(q5)R^(n5),—NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5), —C(O)OR^(n5), or—C(O)NR^(q5)R^(r5), wherein any (C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴is optionally substituted with 1, 2, 3, 4 or 5 Z^(4a) groups.

In certain embodiments, each Z⁴ is independently (C₁-C₆)alkyl orhalogen, wherein any (C₁-C₆)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 halogen, which may be the same or different. In certainembodiments, each Z⁴ is independently (C₁-C₄)alkyl or halogen, whereinany (C₁-C₆)alkyl of Z⁴ is optionally substituted with 1, 2, 3, 4 or 5halogen, which may be the same or different. In certain embodiments,each Z⁴ is independently (C₁-C₃)alkyl or halogen, wherein any(C₁-C₃)alkyl of Z⁴ is optionally substituted with 1, 2, 3, 4 or 5halogen, which may be the same or different.

In certain embodiments, each Z⁴ is independently fluoro,trifluoromethyl, or difluoromethyl.

In certain embodiments of formula III, R¹ optionally substituted with 1,2, 3, 4, or 5 Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ optionally substituted with 1, 2, 3, 4, or 5Z⁴ groups is

In certain embodiments, R¹ is

optionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups.

In certain embodiments, R¹ is

optionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups.

In certain embodiments of formula III, each Z⁴ is independently(C₁-C₆)alkyl or halogen, wherein any (C₁-C₆)alkyl of Z⁴ is optionallysubstituted with 1, 2, 3, 4 or 5 halogen, which may the same ordifferent.

In certain embodiments, each Z⁴ is independently (C₁-C₆)alkyl, —CN, orhalogen, wherein any (C₁-C₆)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 halogen, which may the same or different.

In certain embodiments, each Z⁴ is independently fluoro,trifluoromethyl, or difluoromethyl.

In certain embodiments, each Z⁴ is independently fluoro,trifluoromethyl, —CN, or difluoromethyl.

In certain embodiments of Formula III, Z¹ is phenyl, 5-14 memberedheteroaryl, or 3-14 membered heterocycle, wherein any phenyl, 5-14membered heteroaryl, or 3-14 membered heterocycle of Z¹ is optionallysubstituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is phenyl, 5-12 membered heteroaryl, or 3-12membered heterocycle, wherein any phenyl, 5-12 membered heteroaryl, or3-12 membered heterocycle of Z¹ is optionally substituted with 1, 2, 3,4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is phenyl, 5-14 membered heteroaryl, or 3-14membered heterocycle, wherein any phenyl, 5-14 membered heteroaryl, or3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2, 3,4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is phenyl, 5-12 membered heteroaryl, or 3-12membered heterocycle, wherein any phenyl, 5-12 membered heteroaryl, or3-12 membered heterocycle of Z¹ is optionally substituted with 1, 2, 3,4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle have 1-11 carbon atoms and 1-5heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle have 1-11 carbon atoms and 1-5heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle have 4-11 carbon atoms and 1-3heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle, whereinthe 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle have 4-11 carbon atoms and 1-3heteroatoms in the ring system, and wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is 8-10 membered bicyclic-heteroaryl or 8-10membered bicyclic-heterocycle, wherein any from 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is 8-10 membered bicyclic-heteroaryl or 8-10membered bicyclic-heterocycle, wherein any from 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In certain embodiments, Z¹ is 8-10 membered bicyclic-heteroaryl or 8-10membered bicyclic-heterocycle, wherein the 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle has 3-9 carbonatoms and 1-5 heteroatoms in the ring system, and wherein any 8-10membered bicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle of Z¹is optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b) groups.

In certain embodiments, Z¹ is 8-10 membered bicyclic-heteroaryl or 8-10membered bicyclic-heterocycle, wherein the 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle has 3-9 carbonatoms and 1-5 heteroatoms in the ring system, and wherein any 8-10membered bicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle of Z¹is optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In certain embodiments of formula III, Z¹ is not substituted withZ^(1b).

In certain embodiments of formula III, each Z^(1a) is independently oxo,(C₃-C₇)carbocycle, halogen, —CN, —O—(C₁-C₈)alkyl, NR^(q1)R^(r1),NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1), —NR^(r1)CONR^(q1)R^(r1),—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), or —C(O)NR^(q1)R^(r1).

In certain embodiments, each Z^(1a) is independently—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), or halogen. In certainembodiments, each Z^(1a) is independently halogen or—NR^(n1)S(O)₂R^(p1). In certain embodiments, each Z^(1a) isindependently halogen or —NR^(n1)S(O)₂NR^(q1)R^(r1).

In certain embodiments, Z¹ is substituted with 2 Z^(1a) groups, whereineach Z^(1a) is independently —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂NR^(q1)R^(r1), or halogen.

In certain embodiments, each Z^(1a) is independently halogen or—NR^(n1)S(O)₂R^(p1) and each Z^(1b) is (C₁-C₈)alkyl, which may be sameor different.

In certain embodiments, Z^(1a) is —NR^(n1)S(O)₂R^(p1) or—NR^(n1)S(O)₂NR^(q1)R^(r1). In certain embodiments, Z^(1a) is halogen.In certain embodiments, Z^(1a) is —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), or —NR^(n1)CONR^(q1)R^(r1).

In certain embodiments, Z^(1a) is halogen, —OR^(n1), or—C(O)NR^(q1)R^(r1).

In certain embodiments, Z^(1a) is halogen or —C(O)NR^(q1)R^(r1).

In certain embodiments, Z^(1a) is halogen, —OH, or —C(O)NH₂.

In certain embodiments, Z^(1a) is fluoro, —OH, or —C(O)NH₂.

In certain embodiments, each Z^(1b) is (C₁-C₈)alkyl, which may be sameor different.

In certain embodiments, each Z^(1b) is independently methyl ordifluoromethyl.

In certain embodiments of formula III, Z¹ is

optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) or Z^(1b).

In certain embodiments, Z¹ is

wherein each Z^(1w) is independently Z^(1a), Z^(1b), or H. In certainembodiments, each Z^(1a) is independently halogen, —CN, —OR^(n1),—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1),—NR^(n1)COR^(p1), —NR^(n1)CONR^(q1)R^(r1), or —NR^(n1)CO₂R^(p1); eachZ^(1b) is independently (C₁-C₈alkyl), wherein the (C₁-C₈alkyl) isoptionally substituted with 1, 2, or 3 halogen, which are the same ordifferent; and at least one of Z^(1w) is Z^(1a) or Z^(1b). In certainembodiments, at least two of Z^(1x) are independently Z^(1a). In certainembodiments, each Z^(1a) is independently halogen, —NR^(n1)S(O)₂R^(p1),or —NR^(n1)S(O)₂NR^(q1)R^(r1).

In certain embodiments, Z¹ is

wherein each Z^(1a) is independently halogen, —NR^(n1)S(O)₂R^(p1) or—NR^(n1)S(O)₂NR^(q1)R^(r1).

In certain embodiments, Z¹ is

, optionally substituted with 1, 2, 3, or 4 Z^(1a) or Z^(1b).

In certain embodiments, Z¹ is

In certain embodiments, Z¹ optionally substituted with 1, 2, 3, 4, or 5Z^(1a) or Z^(1b) groups is

In certain embodiments, Z¹ optionally substituted with 1, 2, 3, 4, or 5Z^(1a) or Z^(1b) groups is

In certain embodiments, Z¹ optionally substituted with 1, 2, 3, 4, or 5Z^(1a) or Z^(1b) groups is

In certain embodiments, Z¹ optionally substituted with 1, 2, 3, 4, or 5Z^(1a) or Z^(1b) groups is

In certain embodiments, Z¹ optionally substituted with 1, 2, 3, 4, or 5Z^(1a) or Z^(1b) groups is

In certain embodiments, Z¹ is

In certain embodiments, Z²-A-Z¹ is:

In one variation of formula III, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and R¹ is a 5-12 membered heteroaryl, optionallysubstituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be the same ordifferent. In another variation, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl, wherein any 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl of R¹ isoptionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups. In anothervariation, A is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; R¹ isa 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl, wherein any 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl of R¹ is optionally substituted with1, 2, 3, 4, or 5 Z⁴ groups; and each Z⁴ is independently fluoro,trifluoromethyl, or difluoromethyl.

In one variation of formula III, A is pyridinyl; and R¹ is a 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein any 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with 1, 2, 3, 4, or5 Z⁴ groups, which may be the same or different.

In one variation of formula III, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyridinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyrimidinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyrazinyl; and R² is 3,5-difluorophenyl. In another variation, A ispyridazinyl; and R² is 3,5-difluorophenyl.

In one variation of formula III, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and Z¹ is phenyl, 5-6 membered monocyclic-heteroaryl,8-10 membered bicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle,or 9-12 membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups, which may bethe same or different. In another variation, A is pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl; and Z¹ is phenyl, optionallysubstituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In another variation, Ais pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; and Z¹ is 5-6membered monocyclic-heteroaryl or 8-10 membered bicyclic-heteroaryl,wherein any 5-6 membered monocyclic-heteroaryl or 8-10 memberedbicyclic-heteroaryl of Z¹ is optionally substituted with 1, 2, 3, 4 or 5Z^(1a) groups. In another variation, A is pyridinyl, pyrimidinyl,pyrazinyl or pyridazinyl; and Z¹ is 8-10 membered bicyclic-heterocycleor 9-12 membered tricyclic-heterocycle wherein any 8-10 memberedbicyclic-heterocycle or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In one variation of formula III, A is pyridinyl; and Z¹ is phenyl, 5-6membered monocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10membered bicyclic-heterocycle, or 9-12 membered tricyclic-heterocyclewherein any phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups, which may be the same or different. Inanother variation, A is pyridinyl; and Z¹ is phenyl, optionallysubstituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In another variation, Ais pyridinyl; and Z¹ is 5-6 membered monocyclic-heteroaryl or 8-10membered bicyclic-heteroaryl, wherein any 5-6 memberedmonocyclic-heteroaryl or 8-10 membered bicyclic-heteroaryl of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups. In anothervariation, A is pyridinyl; and Z¹ is 8-10 membered bicyclic-heterocycleor 9-12 membered tricyclic-heterocycle wherein any 8-10 memberedbicyclic-heterocycle or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In one variation of formula III, A is pyridinyl, pyrimidinyl, pyrazinylor pyridazinyl; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,which may be the same or different, and wherein any (C₂-C₈)alkynyl of Z²is optionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups, which maybe the same or different. In another variation, A is pyridinyl; and Z²is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups. In another variation, A is pyrimidinyl; and Z² is(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups. In anothervariation, A is pyrazinyl; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,or —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups. In another variation, A is pyridazinyl; and Z² is(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups.

In one variation of formula III, A is pyridinyl substituted with one Z¹moiety, one Z² moiety and no (zero) Z³ moieties; and Z² is(C₂-C₈)alkynyl or aryl, which Z² may be optionally substituted asprovided by formula III. In another variation, A is pyridinylsubstituted with one Z¹ moiety, one Z² moiety and no (zero) Z³ moieties;and Z² is (C₂-C₈)alkynyl, which Z² may be optionally substituted asprovided by formula III. In a particular variation, A is pyridinylsubstituted with one Z¹ moiety, one Z² moiety at the position alpha tothe nitrogen atom of the pyridinyl ring, and no (zero) Z³ moieties,wherein Z² is (C₂-C₈)alkynyl, which Z² may be optionally substituted asprovided by formula III.

In one variation of formula III, R¹ is a 5-12 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be thesame or different; and Z¹ is phenyl, 5-6 membered monocyclic-heteroaryl,8-10 membered bicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle,or 9-12 membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups, which may bethe same or different. In another variation, R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl, wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups; and Z¹is phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups.

In one variation of formula III, R¹ is a 8-12 memberedbicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl, wherein any8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroarylof R¹ is optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups, whichmay be the same or different; and Z¹ is 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle wherein any8-10 membered bicyclic-heteroaryl or 8-10 membered bicyclic-heterocycleof Z¹ is optionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups,which may be the same or different.

In one variation of formula III, R¹ is a 5-12 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 Z⁴ groups, which may be thesame or different; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups, which may be the same or different. In anothervariation, R¹ is a 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl wherein any 8-12 membered bicyclic-heteroaryl or8-12 membered tricyclic-heteroaryl of R¹ is optionally substituted with1, 2, 3, 4, or 5 Z⁴ groups; and Z² is (C₂-C₈)alkynyl, 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, 3-12 memberedC-linked-heterocycle, or —C(O)NR^(q3)R^(r3), wherein any 6-12 memberedaryl, 5-12 membered C-linked-heteroaryl, or 3-12 memberedC-linked-heterocycle of Z² is optionally substituted with 1, 2, 3, 4 or5 Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2c) group.

In one variation of formula III, Z¹ is phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with 1,2, 3, 4 or 5 Z^(1a) groups, which may be the same or different; and Z²is (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,which may be the same or different, and wherein any (C₂-C₈)alkynyl of Z²is optionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups, which maybe the same or different.

In one variation of formula III, Z¹ is bicyclic-heteroaryl optionallysubstituted with 1, 2, 3, 4 or 5 Z^(1a) groups, which may be the same ordifferent; and Z² is (C₂-C₈)alkynyl optionally substituted with 1, 2, 3,4 or 5 Z^(2c) groups, which may be the same or different.

In one variation of formula III, R¹ is a 5-12 membered heteroaryl; Z¹ isphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle, or 9-12membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle, or 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1a) groups, which may bethe same or different; and Z² is (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,or —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,which may be the same or different, and wherein any (C₂-C₈)alkynyl of Z²is optionally substituted with 1, 2, 3, 4 or 5 Z^(2c) groups, which maybe the same or different.

In certain embodiments of formula III,

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith 1 or 2 Z³ groups, which may be the same or different;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, which may be the same or different;

R² is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogen, whichmay be the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), which may be the same or different;

each Z^(1a) is independently oxo, (C₃-C₇)carbocycle, halogen, —CN,—O—(C₁-C₈)alkyl, —OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —NR^(q1)R^(r1),—NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1),—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), or —C(O)NR^(q1)R^(r1);

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which may be the same or different;

each R^(n1) is independently H or (C₁-C₈)alkyl;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 (C₁-C₈)alkyl, which may be the same or different, and wherein any(C₁-C₈)alkyl of R^(p1) is optionally substituted with 1, 2, 3, 4 or 5halogen, hydroxyl, —O(C₁-C₈)alkyl, or —NR^(q2)R^(r2), which may be thesame or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or 3-7-membered heterocycle, wherein any (C₁-C₈)alkylof R^(q1) or R^(r1) is optionally substituted with 1, 2, 3, 4 or 5halogen or —CN, which may be the same or different, or R^(q1) and R^(r1)together with the nitrogen to which they are attached form a 5, 6, or7-membered heterocycle, wherein the 5, 6, or 7-membered heterocycle isoptionally substituted with 1, 2, 3, 4 or 5 (C₁-C₈)alkyl, which may bethe same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,which may be the same or different, and wherein any (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3, 4, or 5Z^(2c) groups, which may be the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2c) is independently oxo, halogen, —CN, —OR^(n4), NR^(q4)R^(r4),—NR^(n4)COR^(p4), —NR^(n4)CO₂R^(p4), —NR^(n4)S(O)₂R^(p4), —C(O)R^(n4),—C(O)OR^(n4) or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, or (C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl, or(C₁-C₄)heteroalkyl;

each Z³ is independently a (C₁-C₄)heteroalkyl or halogen;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5) wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, which may be the same or different;

each Z^(4a) is independently halogen, —CN, or —OR^(n6); and

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl.

In certain embodiments of formula III,

A¹ is CH, C—Z³, or nitrogen;

A² is CH or nitrogen;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl,or 3-12 membered heterocycle of R¹ is optionally substituted with 1, 2,3, 4 or 5 Z⁴ groups, which may be the same or different;

each R^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl;

Z¹ is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 memberedheterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl,or 3-14 membered heterocycle of Z¹ is optionally substituted with 1, 2,3, 4 or 5 Z^(1a) or Z^(1b), which may be the same or different;

each Z^(1a) is independently oxo, (C₃-C₇)carbocycle, halogen, —CN,—O—(C₁-C₈)alkyl, —OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —NR^(q1)R^(r1),—NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1),—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), or —C(O)NR^(q1)R^(r1);

each Z^(1b) is independently (C₁-C₈)alkyl optionally substituted with 1,2, 3, 4 or 5 halogen, which may be the same or different;

each R^(n1) is independently H or (C₁-C₈)alkyl;

each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 (C₁-C₈)alkyl, which may be the same or different, and wherein any(C₁-C₈)alkyl of R^(p1) is optionally substituted with 1, 2, 3, 4 or 5halogen, hydroxyl, —O(C₁-C₈)alkyl, or —NR^(q2)R^(r2), which may be thesame or different;

each R^(q1) and R^(r1) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or 3-7-membered heterocycle, wherein any (C₁-C₈)alkylof R^(q1) or R^(r1) is optionally substituted with 1, 2, 3, 4 or 5halogen or —CN, which may be the same or different, or R^(q1) and R^(r1)together with the nitrogen to which they are attached form a 5, 6, or7-membered heterocycle, wherein the 5, 6, or 7-membered heterocycle isoptionally substituted with 1, 2, 3, 4 or 5 (C₁-C₈)alkyl, which may bethe same or different;

each R^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, or R^(q2) and R^(r2) together with the nitrogen towhich they are attached form a 5, 6, or 7-membered heterocycle;

Z² is (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R^(n3), or—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, or 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with 1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups,which may be the same or different, and wherein any (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3, 4, or 5Z^(2c) groups, which may be the same or different;

each R^(n3) is independently H or (C₁-C₄)alkyl;

each R^(q3) and R^(r3) is independently H or (C₁-C₄)alkyl;

each Z^(2b) is independently oxo, (C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or(C₁-C₄)haloalkyl;

each Z^(2c) is independently oxo, halogen, —CN, —OR^(n4), NR^(q4)R^(r4),—NR^(n4)COR^(p4), —NR^(n4)CO₂R^(p4), —NR^(n4)S(O)₂R^(p4), —C(O)R^(n4),—C(O)OR^(n4) or —C(O)NR^(q4)R^(r4);

each R^(n4) is independently H, (C₁-C₄)alkyl, or (C₁-C₄)heteroalkyl;

each R^(p4) is independently (C₁-C₈)alkyl;

each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl, or(C₁-C₄)heteroalkyl;

Z³ is independently a (C₁-C₄)heteroalkyl or halogen;

each Z⁴ is independently oxo, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, halogen,—CN, —OR^(n5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5),—C(O)R^(n5), —C(O)OR^(n5), or —C(O)NR^(q5)R^(r5), wherein any(C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴ is optionally substituted with1, 2, 3, 4 or 5 Z^(4a) groups, which may be the same or different;

each Z^(4a) is independently halogen, —CN, or —OR^(n6); and

each R^(n5), R^(p5), R^(q5), R^(r5), and R^(n6) is independently H or(C₁-C₄)alkyl;

each Z⁵ is independently halogen, which may be same or different; and

n is 0, 1, 2, or 3.

In one embodiment the compound of formula I is selected from:

and pharmaceutically acceptable salts thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound or a pharmaceutically acceptable saltthereof is:

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is:

or a pharmaceutically acceptable salt thereof.

General Synthetic Procedures

The following schemes describe methods that are useful for preparingcompounds of formula I. The following schemes similarly describe methodsthat are useful for preparing compounds of formula III.

Scheme 1 describes a general stereoselective route which is used toprepare compounds of formula I. The scheme is also be used to preparecompounds of formula III. Heteroaryl acids of formula A1 (where Xrepresents diversifiable chemical group such as NH₂, SH, or halogen thatare suitably protected) are converted to the corresponding aldehydesthen condensed with a chiral auxiliary to provide a stereoselectiveaddition of a nucleophilic reagent. Depicted in Scheme 1 is theconversion of a heteroaryl acid A1 containing two diversifiablefunctional groups (e.g., X and Br) to the corresponding aldehyde. Thisis followed by the condensation of the aldehyde A3 with (S) tert-butanesulfinamide and the addition of a Grignard reagent to provide a mixtureof A5 and A6 enriched in A5. This mixture is separated by columnchromatography on silica gel to provide pure diastereomers. Removal ofthe auxiliary provides amines A7 and A8 which are coupled to a varietyof carboxylic acids to provide heteroaryl compounds of formula A9 andA10. Diversification of A9 and A10 is accomplished by a variety ofmethods including alkylation, acylation, cyanation, nucleophilicaromatic displacement, and metal catalyzed cross coupling reactions suchas Suzuki couplings, Buchwald-Hartwig type couplings, and Sonogashiracouplings.

Scheme 2 describes a general stereoselective route which can be used toprepare compounds of formulas I and III.

Depicted in Scheme 2 is the protection of amine A7 to a compound offormula B1. This is followed by the conversion of the Br to thecorresponding boronic acid. Diversification of the functional group Xand boronic acid is accomplished by a variety of methods includingalkylation, acylation, cyanation, nucleophilic aromatic displacement,and metal catalyzed cross coupling reactions such as Suzuki couplings,Buchwald-Hartwig type couplings, and Sonogashira couplings to providecompounds of formulas B3 and B4. Deprotection followed by amideformation with a variety of carboxylic acids provides compounds offormula I.

Combination Therapy

In one embodiment, the invention provides a method for treating an HIVinfection, comprising administering to a patient in need thereof atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents which are suitable for treating an HIV infection.

A compound as disclosed herein (e.g., a compound of any of formulas Iand III or a pharmaceutically acceptable salt thereof) may be combinedwith one or more additional therapeutic agents in any dosage amount ofthe compound (e.g., from 50 mg to 300 mg of compound).

In one embodiment, a method for treating or preventing an HIV infectionin a human having or at risk of having the infection is provided,comprising administering to the human a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents.

In one embodiment, the invention provides pharmaceutical compositionscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with at least one additional therapeuticagent, and a pharmaceutically acceptable carrier. For example, thetherapeutic agent used in combination with the compound disclosed hereincan be any anti-HIV agent.

In one embodiment, combination pharmaceutical agents comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one or more additional therapeutic agentsare provided.

One embodiment provides pharmaceutical compositions comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with at least one additional therapeutic agent,and a pharmaceutically acceptable carrier. In one embodiment, theadditional therapeutic agent may be an anti-HIV agent. For example, insome embodiments, the additional therapeutic agent is selected from thegroup consisting of HIV protease inhibiting compounds (HIV proteaseinhibitors), HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, HIVnon-catalytic site (or allosteric) integrase inhibitors, entryinhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusioninhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerizationinhibitors or capsid disrupting compounds such as those disclosed in US2013/0165489 (University of Pennsylvania), and WO 2013/006792 (PharmaResources), pharmacokinetic enhancers, and other drug for treating HIV,and combinations thereof.

In further embodiments, the additional therapeutic agent is selectedfrom one or more of:

(1) HIV protease inhibitors selected from the group consisting ofamprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase selected from the group consisting of capravirine,emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A,etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120,rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806,KM023 and MK-1439;

(3) HIV nucleoside inhibitors of reverse transcriptase selected from thegroup consisting of zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,apricitibine (AVX754), amdoxovir, KP-1461, GS-9131 (Gilead Sciences) andfosalvudine tidoxil (formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase selected from thegroup consisting of tenofovir, tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide,GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovirdipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

(5) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011, elvitegravir, dolutegravir and GSK-744;

(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)including, but not limited to, BI-224436, CX0516, CX05045, CX14442,compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO2012/003498 (Gilead Sciences) each of which is incorporated by referencein its entirety herein;

(7) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(8) the CXCR4 inhibitor AMD-070;

(9) the entry inhibitor SP01A;

(10) the gp120 inhibitor BMS-488043;

(11) the G6PD and NADH-oxidase inhibitor immunitin;

(12) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798(Pfizer), and CCR5 mAb004;

(13) CD4 attachment inhibitors selected from the group consisting ofibalizumab (TMB-355) and BMS-068 (BMS-663068);

(14) pharmacokinetic enhancers selected from the group consisting ofcobicistat, ritonavir, and SPI-452; and

(15) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS119, ALG 889, andPA-1050040 (PA-040).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with two, three,four or more additional therapeutic agents. In certain embodiments, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with two additional therapeutic agents. In otherembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with three additional therapeuticagents. In further embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with fouradditional therapeutic agents. The two, three four or more additionaltherapeutic agents can be different therapeutic agents selected from thesame class of therapeutic agents, or they can be selected from differentclasses of therapeutic agents. In a specific embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with an HIV nucleotide inhibitor of reverse transcriptase andan HIV non-nucleoside inhibitor of reverse transcriptase. In anotherspecific embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In afurther embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, an HIV non-nucleoside inhibitor of reversetranscriptase, and an HIV protease inhibiting compound. In an additionalembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleotide inhibitor ofreverse transcriptase, an HIV non-nucleoside inhibitor of reversetranscriptase, and a pharmacokinetic enhancer.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate,tenofovir disoproxil, tenofovir alafenamide fumarate, tenofoviralafenamide hemifumarate, or tenofovir alafenamide. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, or tenofovir alafenamide. In aspecific embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with emtricitibine, abacavir orlamivudine.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one of:tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide and one of:emtricitibine, abacavir or lamivudine. In a specific embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with one of: tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide fumarate, ortenofovir alafenamide and one of: emtricitibine or abacavir.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 5-30 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamideand 200 mg emtricitabine. In some embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide and 200 mg emtricitabine. In some embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with 10 mg tenofovir alafenamide fumarate, tenofoviralafenamide hemifumarate, or tenofovir alafenamide and 200 mgemtricitabine. In some embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 25 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of any of formulas I and III or apharmaceutically acceptable salt thereof) may be combined with theagents provided herein in any dosage amount of the compound (e.g., from50 mg to 300 mg of compound) the same as if each combination of dosageswere specifically and individually listed.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 200-400 mg tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovirdisoproxil and 200 mg emtricitabine. In some embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400;300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil and 200 mgemtricitabine. In some embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of any of formulas I and III or apharmaceutically acceptable salt thereof) may be combined with theagents provided herein in any dosage amount of the compound (e.g., from50 mg to 300 mg of compound) the same as if each combination of dosageswere specifically and individually listed.

In some embodiments, one or more of the compounds disclosed herein arecombined with one or more other active therapeutic agents in a unitarydosage form for simultaneous or sequential administration to a patient.In certain embodiments, a pharmaceutical composition including one ormore of the compounds disclosed herein combined with one or more otheractive therapeutic agents is provided. In certain embodiments, thecompounds disclosed herein are combined with one or more other activetherapeutic agents in a solid dosage form. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

In some embodiments, one or more of the compounds disclosed herein areco-administered with one or more other active therapeutic agents.Co-administration of a compound disclosed herein with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound disclosed herein and one or more otheractive therapeutic agents, such that therapeutically effective amountsof disclosed herein and one or more other active therapeutic agents areboth present in the body of the patient.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents such as those disclosed above.

Pharmaceutical Formulations

The compounds disclosed herein are formulated with conventional carriers(e.g., inactive ingredient or excipient material) which will be selectedin accord with ordinary practice. Tablets will contain excipientsincluding glidants, fillers, binders and the like. Aqueous formulationsare prepared in sterile form, and when intended for delivery by otherthan oral administration generally will be isotonic. All formulationswill optionally contain excipients such as those set forth in theHandbook of Pharmaceutical Excipients (1986). Excipients includeascorbic acid and other antioxidants, chelating agents such as EDTA,carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. One embodimentprovides the formulation as a solid dosage form including a solid oraldosage form. The pH of the formulations ranges from about 3 to about 11,but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers and optionallyother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipients, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations described herein that are suitable for oral administrationmay be presented as discrete units including but not limited tocapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient.

Pharmaceutical formulations disclosed herein comprise one or morecompounds disclosed herein together with one or more pharmaceuticallyacceptable carriers or excipients and optionally other therapeuticagents. Pharmaceutical formulations containing the active ingredient maybe in any form suitable for the intended method of administration. Whenused for oral use for example, tablets, troches, lozenges, aqueous oroil suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups or elixirs may be prepared. Compositions intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, lactose monohydrate, croscarmellose sodium, povidone, calciumor sodium phosphate; granulating and disintegrating agents, such asmaize starch, or alginic acid; binding agents, such as cellulose,microcrystalline cellulose, starch, gelatin or acacia; and lubricatingagents, such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In some embodiments, a dosage form(e.g., for oral administration to humans) contains: from 10 mg to 1000mg or from 50 mg to 1000 mg or from 100 mg to 1000 mg or from 200 mg to1000 mg or from 300 mg to 1000 mg or from 10 mg to 800 mg or from 10 mgto 600 mg or from 10 mg to 500 mg or from 10 mg to 400 mg or from 10 mgto 300 mg or from 50 mg to 800 mg or from 100 mg to 600 mg or from 150mg to 500 mg or from 200 mg to 400 mg or from 50 mg to 500 mg or from 10mg to 300 mg or from 50 mg to 300 mg or from 10 mg to 200 mg or from 50mg to 200 mg or from 100 mg to 300 mg or from 100 mg to 200 mg or from200 mg to 300 mg of active material (e.g., a compound of any of formulaeI or III). In some embodiments, a dosage form for oral administration tohumans contains at least any of 10, 25, 50, 100, 150, 200, 250 or 300 mgand no more than 500 or 800 or 1000 mg of active material (e.g., from atleast 50 mg to no more than 500 mg). In some embodiments, a dosage formfor oral administration to humans contains at least any of 10, 25, 50,100, 150, 200, 250 or 300 mg or no more than 500 or 800 or 1000 mg ofactive material. In some embodiments, a dosage form for oraladministration to humans contains any of 10, 25, 50, 100, 150, 200, 250,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or1000 mg of active material. It is understood that a dosage form in anamount provided herein may be administered to a patient (e.g., a humanin need thereof) in accordance with a dosing regimen provided herein,such as once, twice or thrice daily dosing. In one aspect, a dosingregimen provides for administration of at least 10 mg and no more that1,000 mg of active material (e.g., a compound of any of formulas I orIII) daily, and it is understood that the amount may be provided in anysuitable dosage form and amount (e.g., 500 mg twice daily or 1,000 mgonce daily would provide the same amount of 1,000 mg/day dosing). Theinvention embraces once daily dosing to an individual (e.g., a human inneed thereof) of a dosage form of compound (e.g., a compound of any offormulas I or III) containing at least 50 mg and not more than 300 mg ofcompound. In certain embodiments, the carrier material varies from about5 to about 95% of the total compositions (weight:weight).

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds disclosed herein (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds disclosed herein is that they are orally bioavailableand can be dosed orally.

Dosing Regimen

The compound, such as a compound of any of Formulas I and III, may beadministered to an individual in accordance with an effective dosingregimen for a desired period of time or duration, such as at least aboutone month, at least about 2 months, at least about 3 months, at leastabout 6 months, or at least about 12 months or longer. In one variation,the compound is administered on a daily or intermittent schedule for theduration of the individual's life.

The dosage or dosing frequency of a compound of any of Formulas I andIII may be adjusted over the course of the treatment, e.g., based on thejudgment of the administering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In one aspect, the compound is administered oncedaily. In one aspect, the compound is administered twice a day. In oneaspect, the compound is administered three times daily. It is understoodthat the compound may be administered in any dosage amount providedherein, such as a dosage amount that would provide at least 10 mg/daydosing and no more than 1,000 mg/day dosing. Once daily oral dosing isembraced, such as by administering a dosage form containing from 50 mgto 300 mg of compound.

The antiviral properties of a compound of the invention may bedetermined using Test A described below.

Test A: Antiviral Assay in MT4 Cells

For the antiviral assay, 40 μL of a concentration required to achieve afinal effective 1× test concentration of 3-fold serially dilutedcompound in culture medium with 10% FBS was added to each well of a384-well plate (10 concentrations) in quadruplicate. MT-4 cells werenext mixed with HIV-IIIb at an m.o.i of 0.003 for 1 hour, after whichtime 35 μL of virus/cell mixture (2000 cells) was immediately added toeach well containing 40 μL of diluted compound. The plates were thenincubated at 37° C. for 5 days. After 5 days of incubation, 25 μl of 2×concentrated CellTiter-Glo™ Reagent (catalog #G7571, PromegaBiosciences, Inc., Madison, Wis.) was added to each well containing MT-4cells. Cell lysis was carried out by incubating at room temperature for10 min and then chemiluminescence was read. EC50 values were calculatedas the compound concentration that caused a 50% decrease in luminescencesignal, a measure of HIV-1 replication. Percent inhibition ofvirus-induced cell killing calculated from the dose response curve at 2μM and 0.2 μM drug concentration is shown in the table below.

Test B: Cytotoxicity Assay

Compound cytotoxicity and the corresponding CC50 values was determinedusing the same protocol as described in the antiviral assay (Test A)except that uninfected cells were used.

Compounds of the present invention demonstrate antiviral activity (TestA) as depicted in the table below. Shown below are the correspondingvalues for CC50 and percent inhibition of virus-induced cell killing inthe presence of 2 μM and 0.2 μM drug concentration.

% inhibition at % inhibition at Compound 2 μM 0.2 μM CC50 (nM)  1B 77 178569  2 90 79 14347  3D 82 82 4149  4H 74 8 22793  5G 58 3 >53192  6 735 >53192  7 92 8 5664  8C 86 6 21955  9B 95 92 14557  10B 85 1 >53192 11 66 3 >53192  12 58 1 >53192  13 0 — >53192  14E 89 87 6824  15 94 9310261  16C 65 23 3670  17 80 95 12556  18 90 96 6934  19G 93 97 19626 20 80 96 11162  21H 92 92 7628  22C 92 92 4949  23B 88 83 7619  24B 8378 5921  25 89 89 9139  26 100 84 10014  27G 89 89 10412  28 84 71 12175 29B 81 80 15266  30 91 1 8582  31 89 89 8034  32 84 84 9177  33F 93 9312867  34 78 78 8758  35D 91 28 14204  36C 92 88 3150  37F 90 90 6352 38 96 96 13516  39C 91 7 26475  40 87 87 8719  41 98 98 7631  42 100100 11765  43 100 100 15419  44 94 94 6816  45G 92 92 10401  46 89 8710490  47 100 100 21441  48 88 88 23969  49 87 87 23967  50 96 95 11736 51 95 95 11128  52 93 92 31753  53 92 92 8026  54 98 98 8076  55C 92 929559  56F 97 97 18961  57 93 93 7634  58G 95 95 8440  59B 94 94 22443 60 96 86 14337  61B 96 96 14309  62 100 100 5695  63 91 91 8888  64 9898 7696  65 100 85 19301  66 97 97 6956  67I 94 94 21471  68G 96 96 9638 69 77 77 718  70 94 94 9976  71 87 87 9509  72 87 85 5865  73 86 864494  74D 99 99 6905  75 93 92 >40267  76F 98 98 22571  77E 97 96 11804 78 98 98 14418  79 100 100 4716  80 100 96 8579  81 100 100 12466  8299 99 9698  83 94 94 9935  84 100 100 8734  85 96 96 7850  86 99 99 6471 87 96 95 6803  88 100 100 8488  89 95 95 7773  90D 97 97 7620  91E 100100 9382  92 100 100 6244  93 92 92 4809  94 100 100 7577  95 93 93 6513 96 100 100 6998  97 100 100 7596  98 100 100 8410  99B 100 100 6366 10099 99 5136 101 95 95 6526 102 100 100 5815 103 100 100 6792 104 100 1007463 105E 74 — 31484 106E 96 95 12404 107B 95 95 5303 108C 94 94 >53076109 97 97 29567 110E 98 15 >53192 111 90 89 9593 112D 97 97 13891 113D97 — 1092 114G 100 100 14834 115C 91 84 9313 116A 93 62 10484 117F 10093 27833 118 96 96 23924 119C 99 99 9242 120H 88 51 11699 121 98 46 9184122 88 88 9072 123 90 90 7904 124 97 97 9145 125D 97 96 13628 126 92 9215507 127 92 92 8762 128B 94 93 4181 129 82 54 12115 130 85 80 23158131E 96 95 22533 132C 92 92 24161 133 90 90 16784 134 83 82 28027 135B93 93 14242 136D — — 7427 137C 100 93 7881 138 83 61 33392 139B 94 9415437 140M 98 98 20364 141D 100 100 19761 142 92 92 12621 143 98 9811253 144 95 95 16236 145 99 99 8687 146I — — 33468 147 — — >53192 148B83 83 23264 149 86 86 26728 150 87 87 28895 151 92 92 25316 152 89 8911872 153 98 98 18649 154 97 97 12488 155I 99 99 26782 156E 78 78 25584157G 87 87 10904 158G 71 71 26745 159 95 95 27427 160 100 100 20477 16184 84 21843 162 81 81 22412 163 86 79 8853 164 97 96 40504 165 72 725456 166 92 92 24421 167 93 93 34110 168B 90 90 >53192 169 92 92 12421170 88 88 16958 171D — — >42470 172 — — 61 173 92 92 >43678 174 8585 >53192 175 95 95 >46082 176 100 100 17402 177D 100 100 >53192 178 10095 13999 179 100 100 15481 180C 100 100 21252 181C 100 100 >53192 182L100 100 9829 183F 84 84 12400 184 90 90 7694 185C 89 89 18160 186D 87 871517 187G 84 84 19776 188 92 92 26275 189 88 88 17249 190 98 98 13907191 91 91 10142 192 98 95 28776 193 92 92 23055 194 99 84 21268 195 9088 11235 196 92 76 10783 197 63 — 15373 198 98 64 23690 199 95 95 22472200 90 89 12230

The data above represent an average over time of each assay for eachcompound. For certain compounds, multiple assays have been conductedover the life of the project. Thus, the data reported in the tablesinclude the data reported in the priority document, as well as data fromassays run in the intervening period. In the above table, percentinhibition values have been normalized to 100% where the calculation ofpercent inhibition would have resulted in a value greater than 100.

In one embodiment, the compounds demonstrate >10% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >30% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >50% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >70% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >75% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >80% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >85% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >90% inhibition at 2 μM. Inone embodiment, the compounds demonstrate >95% inhibition at 2 μM. It isto be understood that the compounds disclosed herein can be groupedaccording to their % inhibition as described above.

In one embodiment, the compounds demonstrate >10% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >30% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >50% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >70% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >75% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >80% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >85% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >90% inhibition at 0.2 μM.In one embodiment, the compounds demonstrate >95% inhibition at 0.2 μM.It is to be understood that the compounds disclosed herein can begrouped according to their % inhibition as described above.

In one variation, a compound is of any formulae provided herein, whereinthe compound exhibits from 85%-100% inhibition of virus-induced cellkilling at 2 μM. In one variation, a compound is of any formulaeprovided herein, wherein the compound exhibits from 85%-100% inhibitionof virus-induced cell killing at 0.2 μM. In other embodiments, acompound is of any formulae provided herein wherein the compoundexhibits from 50-100, 60-100, 70-100, 80-100, or 90-100% inhibition ofvirus-induced cell killing at 2 μM or at 0.2 μM.

It is understood that % inhibition may be evaluated by techniques knownin the art. In a particular variation, a compound is of any formulaeprovided herein wherein the compound exhibits from 85%-110% inhibitionof virus-induced cell killing at 2 μM or at 0.2 μM as measured by themethod provided in the Test A and Test B sections discussed above.

Percent inhibition was also calculated for certain compounds as comparedto previously published compounds (WO 2013/006738) and is shown below.The percent inhibition of virus-induced cell killing at 2 μM and 0.2 μMwas measured by the method provided in the Test A and Test B sectionsdiscussed above.

Compound Response at 2 μM Response at 0.2 μM

X1 94 21

28 84 71

5G 58  3

X2 91 65

18 90 96

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected and whetherthere are present pharmaceutical carriers and/or pharmaceutically activecompounds, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with practice of the present invention.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

Example 1

Synthesis of(5)-5-bromo-6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)picolinamide(1A)

Compound 5F (100 mg, 0.15 mmol) and CuCN (16 mg, 0.18 mmol) wasdissolved in 0.3 mL of DMF. The reaction mixture was heated at 100° C.overnight. After cooled down to room temperature it was diluted withwater and extracted with EtOAc. The organic phase was dried (Na₂SO₄),filtered and concentrated. The crude material was purified on reversephase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford(S)—N-(1-(3-bromo-6-cyanopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamideand the title product (1A). MS (m/z) 640.05 [M+H]⁺.

Synthesis of(S)-6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide(1B)

The title compound (1B) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand 1A. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (d, J=8.5 Hz, 1H), 8.12 (d, J=7.9Hz, 1H), 8.01 (s, 1H), 7.92-7.77 (m, 2H), 7.56 (d, J=3.5 Hz, 1H),6.97-6.53 (m, 3H), 6.26 (d, J=6.1 Hz, 2H), 5.53 (m, 1H), 5.11 (s, 2H),3.07 (m, 2H), 2.63-2.25 (m, 4H). MS (m/z) 678.08 [M+H]⁺.

Example 2

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)ethyl)acetamide(2)

The title compound (2) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing(4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid and 14D. ¹H NMR (400 MHz,CD₃OD) δ 8.27 (m, 1H), 7.82 (m, 1H), 7.75 (m, 1H), 7.50 (s, 1H), 7.44(m, 2H), 6.86 (m, 1H), 6.61 (m, 2H), 6.32 (m, 1H), 6.15 (m, 2H), 5.21(m, 1H), 4.76 (s, 2H), 3.11 (m, 2H), 2.92 (m, 2H), 2.48 (m, 4H), 1.62(d, J=6.6 Hz, 6H), 1.33 (m, 1H), 1.12 (m, 1H). MS (m/z) 725.14 [M+H]⁺.

Example 3

Synthesis of 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yltrifluoromethanesulfonate (3B)

The mixture of compound 3A (1 g, 5.7 mmol, prepared according to themethod presented in Tetrahedron Letters 50 (2009) 1267-1269), DCM (20mL), and Et₃N (0.9 mL, 6.8 mmol) was cooled to 0° C. using an ice/waterbath. Trifluoromethanesulfonyl chloride (0.91 mL, 8.5 mmol) was addeddropwise via syringe. The mixture was then stirred for 1 h in ambienttemperature. More Trifluoromethanesulfonyl chloride (0.8 mL) was addedand the mixture was stirred at ambient temperature for another hour.Then diluted with DCM (150 mL) and washed with 1.0 N HCl (50 mL),saturated aqueous sodium bicarbonate (1×50 mL), and saturated aqueoussodium chloride (1×50 mL). The organic layer was dried over MgSO₄,filtered through Celite®, and concentrated in vacuo to give the titleproduct (3B). MS (m/z) 308.29 [M+H]⁺.

Synthesis of5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,1′-isoindolin]-3′-one(3C)

In a microwave tube were charged 3B (200 mg, 0.65 mmol),bis(pinacolato)diboron (330 mg, 1.3 mmol) and potassium acetate (191 mg,1.95 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(14 mg, 0.02 mmol) and 1,4-dioxane (8 mL) The mixture was heated up to150° C. for 20 min in a Microwave Synthesizer. Upon completion thesolution was diluted in EtOAc and the organic layer was washed withwater and a saturated NaCl solution, dried over MgSO₄ and concentratedin vacuum to give the title compound as a dark brown solid. A halfamount of the product was purified by silica gel chromatography elutingwith EtOAchexanes to afford the title product. MS (m/z) 286.23 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl)pyridin-2-yl)ethyl)acetamide(3D)

In a microwave tube were charged with 14D (33 mg, 0.05 mmol), 3C (21 mg,0.075 mmol), LiCl (6 mg, 0.15 mmol), K₂CO₃ (21 mg, 0.15 mmol),Pd(PPh₃)₂Cl₂ (3 mg) and Pd(dppf)Cl₂ (3 mg). To the mixture was added 1mL of DME and 0.2 mL of H₂O. The mixture was heated up to 165° C. for 12min in a Microwave Synthesizer. After cooled down and filtered through asyringe filter, purified on reverse phase HPLC eluting with acetonitrileand water (with 0.1% TFA) to afford the title product. ¹H NMR (400 MHz,CD₃OD) δ 8.77 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.32-7.16 (m, 2H), 6.64 (t, J=9.2 Hz,1H), 6.24 (d, J=6.5 Hz, 2H), 5.39 (t, J=7.3 Hz, 1H), 4.86 (s, 2H),3.08-2.92 (m, 2H), 2.58-2.31 (m, 2H), 1.62 (s, 6H), 1.60-1.33 (m, 5H),1.12 (m, 1H).

MS (m/z) 738.15 [M+H]⁺.

Example 4

Synthesis of(S)—N-((3,5-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(4B)

To 3,5-dibromopicolinaldehyde (1.9 g0, 7.17 mmol) in DCM (30 mL) wasadded (S)-2-methylpropane-2-sulfinamide (870 mg, 7.17 mmol) and CuSO₄(2.29 g, 14.3 mmol). The reaction mixture was stirred for 15 h. Solidswere filtered over celite. The solvents were removed in vacuo and theresidue purified by column chromatography on silica to provide 2.6 g ofthe title compound. MS (m/z) 368.9 [M+H]⁺.

Synthesis of(S)—N—((S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(4C)

(S)—N-((3,5-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(2.6 g, 7.1 mmol) was dissolved in THF (24 mL) and cooled to −78° C.(3,5-difluorobenzyl)magnesium bromide (34 mL, 0.25 M in Et₂O) was addeddropwise. The reaction was stirred at −78° C. for 3 hr then let warm to0° C. and quenched. The reaction was partitioned between EtOAc and aq.NH₄Cl. The organics were separated, dried, and removed in vacuo. Theresidue purified by column chromatography on silica to provide the titlecompound. MS (m/z) 496.6 [M+H]⁺.

Synthesis of(S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine (4D)

To(S)—N—((S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(650 mg) dissolved in DCM (3 mL) was added 4N HCl in dioxanes (4 mL).The reaction was stirred for 2 hr at ambient temperature. Solvents wereremoved in vacuo and the crude desired product was used without furtherpurification. MS (m/z) 393.0 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (4E)

(S)-1-(3,5-Dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine (780mg, 1.84 mmol) was combined with di-tert-butyl dicarbonate (400 mg, 1.84mmol) and TEA (515 μL, 3.7 mmol) in DCM (9 mL). The reaction was stirredfor 2 hr at ambient temperature. The reaction was partitioned betweenEtOAc and H₂O. The organics were separated, dried, and removed in vacuo.The residue purified by column chromatography on silica to provide thetitle compound. MS (m/z) 492.9 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(4F)

To (S)-tert-butyl1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (140mg, 0.29 mmol) in THF (18 mL) was added 2-methylbut-3-yn-2-ol (42 μL,0.43 mmol), TEA (0.9 mL), Pd(PPh₃)₂Cl₂ (30 mg) and CuI (16 mg). Thereaction was stirred for 2 hr at ambient temperature and thenpartitioned between EtOAc and H₂O. The organics were separated, dried,and removed in vacuo. The residue purified by column chromatography onsilica to provide the title compound as a mixture with 4E which was usedin the next step. MS (m/z) 496.7 [M+H]⁺.

Synthesis of(S)—N-(1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(4G)

A mixture of (S)-tert-butyl1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamateand (S)-tert-butyl1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (105mg) obtained from the previous step was dissolved in DCM (3 mL) andtreated with 4N HCl in dioxanes (4 mL). The reaction was stirred for 2hr then solvents removed in vacuo. The residue purified by columnchromatography on silica to provide 18 mg of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-3-yl)-2-methylbut-3-yn-2-ol(MS (m/z) 395.0 [M+H]⁺). To(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-3-yl)-2-methylbut-3-yn-2-ol(18 mg, 0.046 mmol) in DMF (1 mL) was added2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (15 mg, 0.05 mmol), iPr₂NEt (17 μL, 0.1 mmol) and HATU (26 mg, 0.07mmol). The reaction was stirred 30 min and then partitioned betweenEtOAc and H₂O. The organics were separated, dried, and removed in vacuo.The crude product was used directly in the next reaction. MS (m/z)679.2[M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(5-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide(4H)

To(S)—N-(1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16 mg, 0.02 mmol) in DME (0.7 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (7 mg,0.03 mmol), Pd(PPh₃)₂Cl₂ (2 mg), LiCl (1 mg), and aq 2M K₂CO₃ (30 μL).The reaction was heated in a microwave reactor to 150° C. for 20 min.The reaction was purified by RP HPLC to provide the desired product. ¹HNMR (400 MHz, Methanol-d₄) δ 8.69 (d, 1H), 7.62-7.49 (m, 2H), 7.43 (s,1H), 7.28 (s, 1H), 6.98-6.58 (m, 4H), 6.26 (d, 2H), 5.34 (d, 2H), 5.18(s, 1H), 5.05 (s, 2H), 4.48 (s, 2H), 3.02 (t, J=7.5 Hz, 3H), 2.49 (s,7H), 1.56 (s, 5H). MS (m/z) 732.1[M+H]⁺.

Example 5

Synthesis of 3,6-dibromo-2-(dibromomethyl)pyridine (5A)

To a solution of 3,6-dibromo-2-methylpyridine (5.2 g, 21 mmol) in CCl₄(50 mL) was added N-bromosuccinimide (7.57 g, 42 mmol) and2,2′-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture washeated at 80° C. overnight and cooled to room temperature. The solid wasremoved by filtration and the filtrate was concentrated under reducedpressure. The product (5A) was obtained after flash chromatographyeluding with 0-10 percent EtOAc in hexane (7.36 g). MS (m/z): 409.66[M+H]⁺

Synthesis of 3,6-dibromopicolinaldehyde (5B)

A solution of silver nitrate (7.6 g, 45 mmol) in water (24 mL) was addeddropwise to a solution of 5A (7.36 g, 18 mmol) in refluxing EtOH (90mL). The mixture was stirred at 80° C. for 5 hours. After the mixturewas cooled to room temperature, it was diluted with water (100 mL),extracted with EtOAc (3 times), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product (5B, 4.6 G) wasdirectly used for next step. MS (m/z): 265.96. [M+H]⁺

Synthesis of(S,Z)—N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(5C)

The title compound (5C) was prepared according to the method presentedfor the synthesis of compound 4B of Example 4 utilizing 5B. MS (m/z)368.86 [M+H]⁺

Synthesis of(S)—N—((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(5D)

The title compound (5D) was prepared according to the method presentedfor the synthesis of compound 4C of Example 4 utilizing 5C. MS (m/z)496.99 [M+H]⁺

Synthesis of(S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (5E)

The title compound (5E) was prepared according to the method presentedfor the synthesis of compound 4D of Example 4 utilizing 5D. MS (m/z)393.29 [M+H]⁺

Synthesis of(S)—N-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(5F)

The title compound (5F) was prepared according to the method presentedfor the synthesis of compound 10A of Example 10 utilizing 5E. MS (m/z)676.96 [M+H]⁺.

Synthesis of (S)-5,5′-(6-(1-(2-(3(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridine-2,5-diyl)bis(2-fluorobenzamide) (5G)

In a microwave tube was charged with 5F (100 mg, 0.15 mmol),(3-carbamoyl-4-fluorophenyl)boronic acid (81 mg, 0.45 mmol), LiCl (19mg, 0.45 mmol), Na₂CO₃ (50 mg, 0.6 mmol) and 5 mg of Pd(PPh₃)₂Cl₂. Tothe mixture was added 1.4 mL of 1,4-dioxane/methanol/H₂O (5/1/1). Themixture was heated up to 170° C. for 15 min in a Microwave Synthesizer.After cooled down and filtered through a syringe filter, purified onreverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA)to afford the title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.90 (d, J=8.6Hz, 1H), 8.74 (dd, J=7.2, 2.4 Hz, 1H), 8.51-8.30 (m, 1H), 7.91 (d, J=8.1Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.41 (m, 2H), 7.23 (dd, J=10.7, 8.5 Hz,1H), 7.02-6.49 (m, 2H), 6.35 (d, J=6.2 Hz, 2H), 5.45 (m, 1H), 5.16-5.02(m, 2H), 3.23-2.97 (m, 2H), 2.49 (m, 4H). MS (m/z) 793.19 [M+H]⁺.

Example 6

Synthesis of(S)—N-(1-(3,6-bis(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(6)

The title compound (6) was prepared according to the method presentedfor the synthesis of compound 5G of Example 5 utilizing6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and 5F.1H NMR (400 MHz, CD₃OD) δ 8.84 (d, J=8.1 Hz, 1H), 8.72 (s, 1H), 8.49 (d,J=7.9 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.72 (dd, J=23.8, 8.0 Hz, 2H),7.60 (d, J=7.9 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 6.97-6.57(m, 2H), 6.33 (m, 2H), 5.49 (m, 2H), 5.10 (s, 2H), 4.57 (s, 2H), 4.49(s, 2H), 3.24-2.95 (m, 2H), 2.47 (m, 4H). MS (m/z) 781.02[M+H]⁺.

Example 7

Synthesis of(S)—N-(1-(3,6-bis(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(7)

The title compound (7) was prepared according to the method presentedfor the synthesis of compound 5G of Example 5 utilizing 65-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand 5F. ¹H NMR (400 MHz, CD₃OD) δ 9.23-9.17 (m, 2H), 9.04 (d, J=8.1 Hz,1H), 8.03 (m, 3H), 7.75 (d, J=8.1 Hz, 1H), 7.61 (dd, J=7.3, 3.5 Hz, 2H),6.93-6.52 (m, 4H), 6.34 (d, J=6.2 Hz, 2H), 5.45 (m, 1H), 5.10 (m, 2H),3.27-3.06 (m, 2H), 2.48 (m, 4H). MS (m/z) 751.22 [M+H]⁺.

Example 8

Synthesis of(S)—N-(1-(5-bromo-2′-methoxy-[2,4′-bipyridin]-6-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(8A) and(S)—N-(1-(2′,5′-di(methoxy-[2,4′-bipyridin]-6-yl))-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(8B)

The title compounds (8A and 8B) were prepared according to the methodpresented for the synthesis of compound 5G of Example 5 utilizing2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2equiv.) and 5F.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2′-methoxy-5-(3-oxoisoindolin-5-yl)-[2,4′-bipyridin]-6-yl)ethyl)acetamide(8C)

The title compound (8C) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing 8A. ¹H NMR (400MHz, CD₃OD) δ 8.85 (d, J=8.1 Hz, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.06 (d,J=8.0 Hz, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J=8.0 Hz,1H), 7.61 (d, J=6.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.38 (s, 1H),6.91-6.44 (m, 2H), 6.29 (d, J=6.3 Hz, 2H), 5.51 (dd, J=14.8, 8.2 Hz,1H), 5.18-4.98 (m, 2H), 4.50 (s, 2H), 4.09 (s, 3H), 3.12 (m, 2H), 2.49(m, 4H). MS (m/z) 757.25 [M+H]⁺.

Example 9

Synthesis of(S)—N-(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(9A)

The title compound (9A) was prepared according to the method presentedfor the synthesis of compound 4F of Example 4 utilizing2-methylbut-3-yn-2-ol and 5F. MS (m/z) 681.17 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide(9B)

The title compound (9B) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing 9A. ¹H NMR (400MHz, CD₃OD) δ 7.63-7.53 (m, 2H), 7.50-7.40 (m, 2H), 7.30 (s, 1H),6.95-6.56 (m, 2H), 6.28 (d, J=6.3 Hz, 2H), 5.39 (t, J=7.4 Hz, 1H), 5.05(s, 2H), 4.48 (s, 2H), 3.13-2.91 (m, 2H), 2.66-2.35 (m, 4H), 1.61 (s,6H). MS (m/z) 732.23 [M+H]⁺.

Example 10

Synthesis of(S)—N-(1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(10A)

To (S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine (380mg, 0.97 mmol) dissolved in DMF (10 mL) was added iPr₂NEt (350 μL, 2mmol) and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (293 mg, 0.97 mmol). HATU (442 mg, 1.16 mmol) was added and thereaction stirred for 30 min. The reaction was partitioned between EtOAcand H₂O. The organics were separated, dried, and removed in vacuo. Theresidue purified by column chromatography on silica to provide the titlecompound. MS (m/z) 677.1 [M+H]⁺.

Synthesis of(S)—N-(1-(3,5-bis(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(10B)

To(S)—N-(1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(50 mg, 0.074 mmol) in DME (0.8 mL) and DMF (0.2 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (48 mg,0.19 mmol), Pd(PPh₃)₂Cl₂ (5 mg), LiCl (2 mg), and aq 2M K₂CO₃ (110 μL).The reaction was heated in a microwave reactor to 150° C. for 20 min.The reaction was purified by RP HPLC to provide the desired product. ¹HNMR (400 MHz, Methanol-d₄) δ 9.02 (d, 1H), 8.11 (d, 1H), 7.97 (dd, 1.7Hz, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.67-7.48 (m, 3H), 7.42 (d, 1H),6.70-6.61 (m, 2H), 6.37-6.30 (m, 2H), 5.44 (t, 1H), 5.07 (s, 2H), 4.51(d, 4H), 3.18-3.01 (m, 3H), 2.50 (dd, 4H). MS (m/z) 798.1[M+H]⁺.

Example 11

Synthesis of(S)—N-(1-(3,5-di(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(11)

The title compound was prepared according to the method presented forthe synthesis of 10B of Example 10 utilizing 10A and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine.¹H NMR (400 MHz, Methanol-d₄) δ 9.10 (s, 1H), 8.62 (s, 1H), 8.56 (s,1H), 8.14 (s, 1H), 8.05-7.94 (m, 2H), 7.58 (dd, 2H), 6.99-6.61 (m, 4H),6.36 (d, 2H), 5.47-5.27 (m, 2H), 5.15-5.00 (m, 2H), 3.24-3.01 (m, 3H),2.66-2.32 (m, 5H). MS (m/z) 751.1[M+H]⁺.

Example 12

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2′-oxo-5-(3-oxoisoindolin-5-yl)-1′,2′-dihydro-[2,4′-bipyridin]-6-yl)ethyl)acetamide(12)

In a microwave tube were charged with(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2′-methoxy-5-(3-oxoisoindolin-5-yl)-[2,4′-bipyridin]-6-yl)ethyl)acetamide(8C, 5 mg), HCl in 1,4-dioxane (4N, 0.3 mL) and ethanol (0.3 mL). Themixture was heated up to 100° C. for 20 min in a Microwave Synthesizer.After cooled down, After cooled down, the solvent was removed and theresidue was purified on reverse phase HPLC eluting with acetonitrile andwater (with 0.1% TFA) to afford the title product. ¹H NMR (400 MHz,CD₃OD) δ 8.88 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H),7.60 (m, 2H), 7.53 (m, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 7.27 (d, J=6.8Hz, 1H), 6.96-6.53 (m, 2H), 6.30 (d, J=6.2 Hz, 2H), 5.49 (m, 1H), 5.09(s, 2H), 4.49 (s, 2H), 3.12 (m, 2H), 2.48 (m, 4H). MS (m/z) 742.99[M+H]⁺.

Example 13

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2,2″-dioxo-1,1″,2,2″-tetrahydro-[4,2′:5′,4″-terpyridin]-6′-yl)ethyl)acetamide(13)

The title compound (13) was prepared according to the method presentedfor the synthesis of compound 12 of Example 12 utilizing 8B. ¹H NMR (400MHz, CD₃OD) δ 8.95 (d, J=7.8 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.71 (d,J=8.1 Hz, 1H), 7.60 (d, J=6.8 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.25 (d,J=6.9 Hz, 1H), 6.98-6.61 (m, 2H), 6.45 (d, J=6.3 Hz, 2H), 6.33 (d, J=6.6Hz, 1H), 6.19 (s, 1H), 5.51 (m, 1H), 5.08 (m, 2H), 3.15 (m, 2H), 2.49(m, 4H). MS (m/z) 705.00 [M+H]⁺.

Example 14

Synthesis of (S)-tert-butyl1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (14A)

The title compound was prepared according to the method presented forthe synthesis of compound 4E of Example 4 utilizing 5E.

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(14B)

The title compound (14B) was prepared according to the method presentedfor the synthesis of compound 4F of Example 4 utilizing2-methylbut-3-yn-2-ol and (S)-tert-butyl(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate. MS(m/z) 496.90 [M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-2-yl)-2-methylbut-3-yn-2-olcompound with 2-methylbut-3-yn-2-ol (1:1) hydrochloride (14C)

The title compound (14C) was prepared according to the method presentedfor the synthesis of compound 4G of Example 4 utilizing 14B. MS (m/z)397.09 [M+H]⁺.

Synthesis ofN—((S)-1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(14D)

The title compound (14D) was prepared according to the method presentedfor the synthesis of compound 4G of Example 4 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and 14C. MS (m/z) 659.23 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxoisoindolin-4-yl)pyridin-2-yl)ethyl)acetamide(14E)

The title compound (14E) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand 14D. ¹H NMR (400 MHz, CD₃OD) δ 8.92 (d, J=8.7 Hz, 1H), 8.00 (s, 2H),7.85 (s, 1H), 7.59 (m, 2H), 7.48 (d, J=7.9 Hz, 1H), 6.77-6.56 (m, 2H),6.28 (d, J=6.3 Hz, 2H), 5.33 (m, 1H), 4.87 (s, 2H), 3.17-2.99 (m, 4H),2.48 (m, 4H), 1.6 (s, 6H), 1.40 (m, 1H), 1.10 (m, 1H). MS (m/z) 697.28[M+H]⁺.

Example 15

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxoisoindolin-4-yl)pyridin-2-yl)ethyl)acetamide(15)

The title compound (15) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing 14D and2,3-dihydro-1H-isoindol-1-one-4-boronic acid pinacol ester. ¹H NMR (400MHz, CD₃OD) δ 7.82 (m, 1H), 7.53 (m, 4H), 6.78 (m, 1H), 6.30 (m, 2H),5.35 (m, 1H), 4.83 (m, 2H), 4.17 (m, 2H), 3.16-3.04 (m, 1H), 2.98 (m,1H), 2.48 (m, 2H), 1.53 (s, 6H), 1.43 (m, 1H), 1.08 (m, 1H). MS (m/z)712.18 [M+H]⁺.

Example 16

Synthesis of(S)—N-(1-(3-bromo-6-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16A)

The title compound (16A) was prepared according to the method presentedfor the synthesis of compound 4F of Example 4 utilizingethynyltrimethylsilane and 5F. MS (m/z) 694.59 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16B)

The title compound (16B) was prepared according to the method presentedfor the synthesis of compound 4H of Example 4 utilizing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand 16A. MS (m/z) 731.22 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6-(1H-1,2,3-triazol-4-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16C)

Compound 16B (75 mg, 0.1 mmol), NaN₃ (13 mg, 0.2 mmol) and NH₄Cl (5 mg,0.1 mmol) were dissolved in DMF (0.5 mL) and stirred at 100° C. forovernight. The reaction mixture was cooled down to room temperature anddiluted with water and extracted with EtOAc. The organic phase was dried(Na₂SO₄), filtered and concentrated. The crude material was purified onreverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA)to afford the title product. ¹H NMR (400 MHz, CD₃OD) δ 9.01 (d, J=7.7Hz, 1H), 8.54 (s, 1H), 7.99 (m, 3H), 7.73 (d, J=8.0 Hz, 1H), 7.59 (d,J=3.5 Hz, 1H), 6.97-6.55 (m, 3H), 6.31 (d, J=6.3 Hz, 2H), 5.45 (m, 1H),5.11 (s, 2H), 3.13 (m, 2H), 2.49 (m, 4H). MS (m/z) 702.02 [M+H]⁺.

Example 17

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)ethyl)acetamide(17)

The title compound was prepared according to the method presented forthe synthesis of compound 4F of Example 4 utilizing8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2,4(1H,3H)-dioneand 14D. ¹H NMR (400 MHz, DMSO) δ 11.36 (d, 1H), 10.12 (d, 1H), 8.87 (m,1H), 7.98 (d, 1H), 7.75-6.70 (m, 7H), 6.47-6.57 (m, 2H), 4.74-4.50 (m,2H), 3.01-2.90 (m, 2H), 2.48-2.60 (m, 2H), 1.49 (s, 6H), 1.45-1.24 (m,1H), 0.96 (m, 1H). MS (m/z) 741.1 [M+H]⁺.

Example 18

Synthesis of5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2-fluorobenzamide(18)

The title compound was prepared according to the method presented forthe synthesis of compound 4F of Example 4 utilizing(3-carbamoyl-4-fluorophenyl)boronic acid and 14D. ¹H NMR (400 MHz, DMSO)δ 9.08 (d, 1H), 7.79-7.14 (m, 8H), 6.92 (m, 1H), 6.62 (d, 2H), 5.12 (m,1H), 4.77-4.83 (m, 2H), 3.01 (m, 2H), 2.55 (m, 1H), 1.51 (s, 6H), 1.38(m, 1H), 0.98 (m, 1H). MS (m/z) 718.2 [M+H]⁺.

Example 19

Synthesis of 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (19B)

To 3-bromo-6-chloro-2-fluorobenzonitrile (10 g, 42.7 mmol) in EtOH (100mL) was added methylhydrazine (9 ml, 171 mmol). The reaction mixture wasstirred for 4 hours at 110° C. The reaction was allowed to slowly coolover 4 hours, then the solids were filtered off and used with no furtherpurification to provide 7 g of the title compound (including minoramounts of the other regioisomer). MS (m/z) 262.0 [M+H]⁺.

Synthesis of4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(19C)

To 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (3 g, 11.5 mmol) indioxane (40 mL) and DMF (25 ml) was added bis(pinacolato)diborane (8.8g, 34.6 mmol), potassium acetate (3.4 g, 34.6 mmol), andtrans-dichlorobis(triphenylphosphine)palladium (II) (486.35 mg, 0.69mmol). The reaction mixture was stirred for 3 hours at 130° C. Thereaction was cooled, diluted with EtOAc, and then the solids werefiltered off over Celite and silica gel eluting with EtOAc. The mixturewas concentrated and purified by flash column chromatography to provide1.8 g of the title compound. MS (m/z) 308.3 [M+H]⁺.

Synthesis ofN-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(19D)

To 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (2.6 g, 8.5 mmol) in DCM(30 mL) was added N,N-Diisopropylethylamine (5.9 ml, 33.8 mmol) then thereaction was cooled in an ice bath and methansulfonyl chloride (2 ml,25.4 mmol) was added. The reaction mixture was stirred for 20 minutes at0° C. The reaction was diluted with water and extracted 2× with DCM. Theorganic layer was dried over sodium sulfate and concentrated. Theresulting mixture was taken up in EtOH (30 ml) and 8 ml of 10N NaOH wasadded. The reaction was followed by LCMS and once done (10 minutes) thereaction was diluted with water and quenched with concentrated HCl to pH2. The mixture was extracted 3× with DCM. The organic layer was driedover sodium sulfate and concentrated until solid starts to fall out. Themixture is then cooled in a brine/ice bath for 20 minutes and filteredto recover desired as two lots and used with no further purification toprovide 2.1 g of the title compound. MS (m/z) 386.4 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(19E)

ToN-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(39 mg, 0.1 mmol) in dioxane (5 mL) and DMF (0.3 ml) was added 14B (50mg, 0.1 mmol), 1N sodium bicarbonate (0.9 ml, 0.9 mmol), anddichlorobis(tricyclohexylphosphine)palladium (II) (1.9 mg, 0.003 mmol).The reaction mixture was stirred for 4 hours at 140° C. The reaction wascooled, diluted with EtOAc and brine. The mixture was extracted 2× withEtOAc, the organic layer was dried over sodium sulfate, was concentratedand purified by flash column chromatography to provide 30 mg of thetitle compound. MS (m/z) 674.7 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamideTFA salt (19F)

To (S)-tert-butyl1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(30 mg, 0.04 mmol) in DCM (4 mL) was added TFA (2 ml). The reactionmixture was stirred for 0.5 hours at RT. The reaction was concentratedand used with no further purification to provide the title compound. MS(m/z) 574.4 [M+H]⁺.

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(19G)

The title compound (19G) was prepared according to the method presentedfor the synthesis of compound 4G of Example 4 utilizing2-((3bS,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamideto provide 20 mg of the title compound. ¹H NMR (400 MHz, Methanol-d₄) δ8.69 (t, 1H), 7.69 (dd, 1H), 7.53 (dd, 1H), 7.17 (s, 1H), 7.06 (d, 1H),6.88-6.52 (m, 2H), 6.44-6.33 (m, 2H), 5.28 (d, 1H), 5.02-4.92 (m, 1H),4.78-4.64 (m, 2H), 3.33 (s, 3H), 3.24 (d, 3H), 3.19-3.08 (m, 2H),3.05-2.92 (m, 2H), 2.44 (ddd, 2H), 1.64 (d, 6H), 1.38 (dt, 1H), 1.02 (s,1H).

MS (m/z) 820.8 [M+H]⁺.

Example 20

Synthesis of(S)—N-(1-(3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(20)

The title compound was prepared according to the method presented forthe synthesis of compound 19G of utilizingN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamideand compound 14B. ¹H NMR (400 MHz, Methanol-d₄) δ 8.69 (t, 1H),7.88-7.80 (dd, 1H), 7.69 (dd, 1H), 7.53 (dd, 1H), 7.20 (s, 1H), 7.09 (d,1H), 6.88-6.52 (m, 2H), 6.38-6.27 (m, 2H), 5.35 (m, 1H), 5.02-4.95 (m,1H), 4.80-4.65 (m, 2H), 3.33 (s, 3H), 3.19-3.08 (m, 4H), 3.05-2.92 (m,2H), 2.44 (m, 2H), 1.64 (d, 6H), 1.38 (m, 1H), 1.02 (m, 1H).

MS (m/z) 786.1 [M+H]⁺.

Example 21

Synthesis of5-bromo-N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (21A)

To a mixture of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (5 g,20 mmol), N,O-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol) andHATU (9.1 g, 24 mmol) in 100 mL of CH₂Cl₂ at 0° C. was addedN,N-diisopropylethylamine (17.4 mL, 100 mmol). The reaction mixture wasallowed to stir at 0° C. for 30 min and then diluted with CH₂Cl₂. It waswashed with water and half brine. The organic layer was separated, driedover MgSO₄, filtered and concentrated. The crude product was purified bysilica gel chromatography to afford the title compound 21A. MS (m/z)292.16 [M+H]⁺.

Synthesis of 5-bromo-2-(methylthio)pyrimidine-4-carbaldehyde (21B)

A solution of5-bromo-N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (21A,8.2 g, 28 mmol) in THF (120 mL) was added dropwise to a suspension oflithium aluminum hydride (1.06 g, 28 mmol) and THF (120 mL) at −78° C.The mixture was stirred for 10 minutes after addition finish. H₂O (1.06mL), 15% aqueous NaOH solution (1.06 mL) and H₂O (3.18 mL) weresuccessively added to the mixture at 0° C. very slowly. The resultingprecipitate was filtered and washed with THF. The filtrate wasconcentrated in vacuo to afford crude of the title compound. MS (m/z):233.14, [M+H]⁺.

Synthesis of(S)—N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide(21C)

Copper(II) sulfate (anhydrous, 8.9 g, 56 mmol) was added to a solutionof 5-bromo-2-(methylthio)pyrimidine-4-carbaldehyde (21B, ˜28 mmol) and(S)-2-methylpropane-2-sulfinamide (3.4 g, 28 mmol) in CH₂Cl₂ (100 mL).The suspension was stirred for 3 days at room temperature. The reactionwas filtered and washed with CH₂Cl₂ (3×20 ml). The filtrate wasconcentrated. The crude product was purified by silica gelchromatography to yield the title compound 21C. MS (m/z) 337.7 [M+H]⁺

Synthesis of(S)—N—((S)-1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(21D)

To a solution of(S)—N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide(21C, 2.97 g. 8.8 mmol) in THF (18 mL) cooled to −78° C. was drop wiseadded 3,5-Difluorobenzylmagnesium bromide (53 mL, 0.25 M in Ether, 13.3mmol). After stirring at −78° C. for 10 min, NH₄Cl (sat. aq.) (10 ml)was added to the reaction and warmed up to ambient temperature.Extracted with EtOAc and the organic layer was dried over Na₂SO₄(s). Thesolvent was removed and the residue was purified by silica gelchromatography to yield 1.44 g of the title compound 21D MS (m/z) 465.87[M+H]⁺

Synthesis of(S)-1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (21E)

Compound 21D (8 g, 17.23 mmol) was dissolved in 35 mL of methanol andcooled to 0° C. To it was added 4N HCl/1,4-dioxane (10.7 mL). Thereaction mixture was allowed to stir for 20 minutes and to it was addeddiethyl ether. The resulting precipitate was collected by vacuumfiltration then dried to afford the title product 21E. MS (m/z) 362.02[M+H]⁺.

Synthesis of(S)—N-(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(21F)

A mixture of2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (604 mg, 2 mmol), compound 21E (793 mg, 2 mmol) and HATU (912 mg,2.4 mmol) in 10 mL of DMF was cooled to 0° C. To it was drop wise addedN,N-diisopropylethylamine (1.05 mL, 6 mmol). The reaction mixture wasallowed to stir at 0° C. for 10 minutes then slowly poured it into icewater with stirring. The resulting precipitate was collected by vacuumfiltration then dried to afford the title product 21F. MS (m/z) 644.22[M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide(21G)

In a microwave tube were charged with compound 21F (300 mg, 0.47 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (181 mg,0.7 mmol) and PdCl₂[P(Cy)₃]₂ (17 mg, 0.023 mmol). To the mixture wasadded 10 mL of 1,4-dioxane and 1.4 mL of sodium bicarbonate aqueoussolution (1M). The mixture was heated to 155° C. for 25 min in amicrowave synthesizer. After cooled to room temperature, it waspartitioned between EtOAc and water. The organic layer was separated andwashed with brine, then dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography to afford the titlecompound 21G. MS (m/z) 697.32 [M+H]⁺).

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide(21H)

To the mixture of solid CuI (3.3 mg, 0.017 mmol), Pd(dppf)Cl₂ (7 mg,0.009 mmol), 2-methylbut-3-yn-2-ol (22 mg, 0.26 mmol) and compound 21G(60 mg, 0.086 mmol) were added THF (1 mL) and Et₃N (0.06 mL, 0.4 mmol).The reaction mixture was heated in a microwave at 160° C. for 20 min.After cooled to room temperature it was diluted with EtOAc. To it wasadded Si-Thiol (130 mg, 1.37 mmol/g) and the mixture was stirred at 40°C. for 1 hour. Then it was filtered and the filtrate was washed with 10%aqueous NH₄OH, water and brine. The organic layer was dried over MgSO₄,filtered, concentrated, and purified by reverse phase HPLC to afford thetitle compound (21H). ¹H NMR (400 MHz, Methanol-d4): δ 9.09 (d), 8.54(s), 7.64 (dd), 7.58 (dd), 7.40 (d), 6.78 (t), 6.67 (tt), 6.43-6.20 (m),5.40 (q), 4.50 (s), 3.05 (d), 2.50 (tdd), 1.62 (s). MS (m/z): 732.99[M+H]⁺.

Example 22

Synthesis ofN—((S)-1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(22A)

The title compound (22A) was prepared according to the method presentedfor the synthesis of compound 21F of Example 21 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 21E. MS (m/z) 624.13 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide(22B)

The title compound (22B) was prepared according to the method presentedfor the synthesis of compound 21G of Example 21 utilizing compound 22Aand 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. MS(m/z) 677.05 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide(22C)

The title compound (22C) was prepared according to the method presentedfor the synthesis of compound 21H of Example 21 utilizing compound 22Band 2-methylbut-3-yn-2-ol. ¹H NMR (400 MHz, Methanol-d4): δ 9.05 (d),8.53 (s), 7.63 (dd), 7.58 (dd), 7.37 (d), 6.75-6.55 (m), 6.41-6.21 (m),5.41 (q), 4.85 (s), 4.50 (s), 3.05 (dd), 2.48-2.45 (m), 1.62 (s), 1.38(q), 1.18-0.97 (m, 1H). MS (m/z) 713.01 [M+H]⁺.

Example 23

Synthesis of5-(4-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-2-(methylthio)pyrimidin-5-yl)-2-fluorobenzamide(23A)

The title compound (23A) was prepared according to the method presentedfor the synthesis of compound 21G of Example 21 utilizing compound 22Aand 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.MS (m/z) 683.06 [M+H]⁺.

Synthesis of5-(4-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-5-yl)-2-fluorobenzamide(23B)

The title compound (23B) was prepared according to the method presentedfor the synthesis of compound 21H of Example 21 utilizing compound 23Aand 2-methylbut-3-yn-2-ol. ¹H NMR (400 MHz, Methanol-d₄): δ 9.09 (t),8.51 (d), 7.46 (ddq), 7.27 (ddd), 6.69 (tt), 6.40 (h), 5.36 (q), 4.84(s), 3.10-3.01 (m), 2.48-2.45 (m), 1.61 (s), 1.38 (q), 1.07 (dd). MS(m/z) 719.06 [M+H]⁺.

Example 24

Synthesis of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one(24A)

To 5-bromoisoquinolin-1(2H)-one (40 mg, 0.18 mmol) in dioxane (1 mL) wasadded bis(pinacolato)diboron (63 mg, 0.25 mmol), and PdCl₂[P(Ph)₃]₂ (6mg, 0.01 mmol). The reaction mixture sealed and heated to 100° C. for 1h. The reaction was cooled to room temperature and telescoped to thenext reaction. MS (m/z) 272.3 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxo-1,2-dihydroisoquinolin-5-yl)pyridin-2-yl)ethyl)acetamide(24B)

To the reaction vial containing 24A (0.18 mmol) was added 14D (50 mg,0.07 mmol), PdCl₂[P(Ph)₃]₂ (5 mg, 0.01 mmol), LiCl (11 mg, 0.22 mmol)and aq 1M NaHCO₃ (0.22 mL, 0.22 mmol). The reaction mixture was sealedand heated in a microwave reactor to 160° C. for 20 min. Upon cooling,the reaction mixture was diluted with EtOAc and washed with threeportions of brine. The organic layer were dried over Na₂SO₄, filtered,concentrated in vacuo, and purified by reverse phase HPLC to provide thetitle compound 24B as a mixture of atropisomers. MS (m/z) 724.2 [M+H]⁺.HPLC retention time 6.95 min and 7.09 min (2-98% acetonitrile:water with0.1% trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18column).

Example 25

Synthesis ofN—((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(25)

The title compound (25) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and 37A. ¹H NMR (400 MHz, cd₃od) δ 9.04-8.52 (m), 7.7-7.61 (m),7.52 (dd), 7.17 (d), 7.04 (t), 7.00-6.90 (m), 6.77-6.66 (m), 6.60 (t),6.48 9 (d), 6.40-6.25 (m), 5.32-5.25 (m), 5.11-5.04 (m), 4.80-4.79 (m),3.22-3.06 (m), 2.96-2.85 (m), 2.52-2.46 (m), 1.64 (s), 1.43-1.39 (m),1.14-1.07 (m). MS (m/z) 726.2 [M+H]⁺.

Example 26

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)acetamide(26)

The title compound (26) was prepared according to the method presentedfor the synthesis of compound 24B of Example 24 utilizing6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-oneMS (m/z) 714.1 [M+H]⁺. HPLC retention time 6.58 min (2-98%acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on aPhenomonex Kinetex C18 column).

Example 27

Synthesis of 3-bromo-6-hydrazinyl-2-methylpyridine (27B)

To 3-bromo-6-chloro-2-methylpyridine (1.53 g, 7.41 mmol) in dioxane (4.5ml) was added hydrazine hydrate (1.8 ml, 37 mmol). The reaction washeated in a microwave reactor at 160° C. for 55 min. After cooling toambient temperature, the reaction mixture was partitioned between EtOAcand saturated aqueous NaCl. The organics were separated and evaporatedin vacuo. The product was used directly in the following step. MS (m/z)202.0 [M+H]⁺.

Synthesis of 6-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(27C)

3-bromo-6-hydrazinyl-2-methylpyridine (4.55 g, 22.52 mmol) was dissolvedin DCE (35 ml) to which trichloromethyl chloroformate (2.72 ml, 22.52mmol) was added. The reaction was stirred at ambient temperature for 1h. Hexanes (15 ml) was added and the solids filtered to provide thedesired product. The eluent was reduced in a volume and a second crop ofprecipitate was isolated. The combined solids were used without furtherpurification. MS (m/z) 228.0 [M+H]⁺.

Synthesis of5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(27D)

6-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.62 g, 15.87mmol) was combined with bis(pinacolato)diboron (6.05 g, 23.81 mmol),KOAc (3.12 g, 31.75 mmol), and PdCl₂(PCy₃)₂ (0.23 g, 0.32 mmol) indioxane (80 ml). Argon was bubbled into the reaction solution for 15min. The reaction was then heated to 85 deg C. for 15 h. AdditionalPdCl₂(PCy₃)₂ (250 mg) was added and the temperature was raised to 125deg C. Heated for 15 h. After cooling to ambient temperature, thereaction was partitioned between EtOAc and water. The organics wereseparated, dried, and removed in vacuo. The residue was suspended inEtOAc (50 ml) and the resultant solids filtered to provide the titlecompound. MS (m/z) 276.2 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)carbamate(27E)

In a microwave reaction vessel, 14B (66 mg, 0.13 mmol) and5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(55 mg, 0.2 mmol) were dissolved in dioxane (2 mL) and treated withaqueous 1M NaHCO₃ (0.4 mL) and PdCl₂(PCy₃)₂ (10 mg). The mixture washeated to 150° C. for 20 min. After cooling to ambient temperature, thereaction was partitioned between EtOAc and water. The organics wereseparated, dried, and removed in vacuo and the residue was purified bycolumn chromatography on silica to provide the title compound as amixture of atropisomers. MS (m/z) 563.8 [M+H]⁺.

Synthesis of(S)-6-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(27F)

The title compound (27F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 19F in Example 19utilizing 27E. MS (m/z) 464.1 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)acetamide(27G)

The title compound (27G) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 37E in Example 37utilizing 27F and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (dd), 7.44-7.54 (m),6.83-6.92 (m), 6.68-6.80 (m), 6.47-6.56 (dd), 5.98 (d), 5.16-5.24 (m),3.13-3.26 (m), 3.03-3.08 (m), 2.45-2.51 (m), 2.37 (s), 2.11 (s),1.36-1.43 (m), 1.05-1.15 (m). MS (m/z) 728.0 [M+H]⁺.

Example 28

Synthesis of (S)-5-(2-(1-(2-(3(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2-fluorobenzamide(28)

The title compound (28) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing(3-carbamoyl-4-fluorophenyl)boronic acid and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.88 (d), 7.55 (d), 7.50-7.36 (m), 7.32(s), 7.23 (dd), 6.94 (d), 6.82 (d), 6.72-6.62 (m), 6.40-6.31 (m),5.40-5.32 (m), 5.22 (s), 5.06 (s), 4.36-4.29 (m), 3.75-3.57 (m),3.14-2.98 (m), 2.66-2.42 (m), 1.62 (s). MS (m/z) 738.2 [M+H]⁺.

Example 29

Synthesis of7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (29A)

To 7-bromo-1H-indazol-3-amine (75 mg, 0.35 mmol) in dioxane (3 mL) wasadded bis(pinacolato)diboron (126 mg, 0.5 mmol), and PdCl₂[P(Ph)₃]₂ (12mg, 0.01 mmol). The reaction mixture sealed and heated to 100° C. for 16h. The reaction was cooled to room temperature and telescoped to thenext reaction. MS (m/z) 260.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(29B)

The title compound (29) was prepared according to the method presentedfor the synthesis of compound 24B of Example 24 utilizing 29A. MS (m/z)712.4 [M+H]⁺. PLC retention time 6.02 min (2-98% acetonitrile:water with0.1% trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18column).

Example 30

Synthesis of5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2,3-difluorobenzamide(30)

The title compound (30) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing5-bromo-2,3-difluorobenzamide and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.80 (d), 7.71-7.65 (m), 7.60-7.50 (m),7.49-7.40 (m), 7.25-7.18 (m), 7.17-7.10 (m), 6.79-6.65 (m), 6.43-6.31(m), 5.33 (m, 1H), 5.03 (s), 4.33-4.30 (m), 3.20-3.00 (m), 2.59-2.45(m), 1.65-1.55 (m), 1.49-1.37 (m), 1.15-1.04 (m). MS (m/z) 736.1 [M+H]⁺.

Example 31

Synthesis of(S)—N-(1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(31)

The title compound (31) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing 37A and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.85 (m), 7.87-7.85 (m), 7.70 (d),7.54-7.46 (d), 7.33 (d), 7.25-7.15 (m), 6.81-6.71 (m), 6.40-6.32 (m),5.35-5.24 (m), 5.03-4.98 (m), 3.19 (s), 3.08-2.95 (m), 2.61-2.40 (m),1.64 (s). MS (m/z) 746.2 [M+H]⁺.

Example 32

Synthesis ofN—((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(32)

The title compound (32) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing 37A. ¹H NMR (400 MHz, cd₃od) δ 8.68 (d), 7.89-7.79(m), 7.74-7.65 (m), 7.59-7.48 (m), 7.29 (d), 7.16-7.11 (m), 6.79-6.60(m), 6.39 (d), 6.35-6.28 (m), 5.27-5.22 (m), 5.06-4.95 (m), 4.73 (d),3.16 (s), 3.13-3.03 (m), 3.02-2.84 (m), 2.50-2.39 (m), 1.64 (s),1.42-1.34 (m), 1.03 (s). MS (m/z) 708.2 [M+H]⁺.

Example 33

Synthesis of 7-bromo-1-methyl-1H-indazol-3-amine (33A)

In a microwave vial a solution of 3-bromo-2-fluorobenzonitrile (2 g, 10mmol) ethanol (10 mL) was treated with methylhydrazine (2.1 mL, 40mmol), sealed, and heated to 120° C. in a microwave reactor for 35minutes. The reaction was concentrated in vacuo and the crude productdissolved with EtOAc (30 mL) and washed with water (30 mL), then 2M NaCl(aq, 30 mL). The organics were dried with Na₂SO₄, filtered, andconcentrated. Product was purified by silica chromatography to give thetitle compound. MS (m/z) 227.1 [M+H]⁺.

Synthesis of N-(7-bromo-1-methyl-1H-indazol-3-yl)methanesulfonamide(33B)

To a stirred solution of 33A (500 mg, 2.21 mmol),4-Dimethylaminopyridine (13.5 mg, 0.11 mmol), andN,N-diisopropylethylamine (714.6 mg, 5.53 mmol) in DCM (20 ml) was addeddropwise methanesulfonyl chloride (532.0 mg, 4.64 mmol) at 0° C. Thereaction was warmed to RT and stirred for 2 h. The reaction was washedwith water, dried with Na₂SO₄, filtered, and concentrated. The crudeproduct dissolved with EtOH (10 mL) and treated with 8N NaOH (1.65 ml).The reaction mixture was heated at 60° C. for 0.5 h. The ethanol wasremoved under vacuum, pH to ˜2 with 1.0HCl then, extracted with EtOAc.The organics were dried with Na₂SO₄, filtered, and concentrated. Theproduct was purified by silica chromatography to give the titlecompound. MS (m/z) 305.9 [M+H]⁺.

Synthesis ofN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(33C)

To 33B (1.2 g, 3.9 mmol) in dioxane (15 mL) was addedbis(pinacolato)diboron (1.9 mg, 5.5 mmol), and PdCl₂[P(Ph)₃]₂ (138 mg,0.19 mmol). The reaction mixture sealed and heated to 100° C. for 1 h.The reaction was cooled to rt and filtered through Celite using ethylacetate to rinse the pad. The collected organic phase was concentratedin vacuo and purified by silica gel chromatography to give the titlecompound. MS (m/z) 352.1 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(33D)

To 14B (250 mg, 0.5 mmol) in dioxane (12 mL) was addedN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(33C, 253 mg, 0.72 mmol), PdCl₂[P(Ph)₃]₂ (35 mg, 0.05 mmol), and aq 1MNaHCO₃ (1.5 mL, 1.5 mmol). The reaction mixture sealed and heated in amicrowave reactor to 150° C. for 20 min. Upon cooling, the reactionmixture was diluted with EtOAc and washed with three portions of brine.The organic layer were dried over Na₂SO₄, filtered, concentrated invacuo, and purified by silica gel column chromatography, eluting with0-100% EtOAc in hexanes to give the title compound 33D as a mixture ofatropisomers.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)methanesulfonamide(33E)

To a solution of 33D (47 mg, 0.07 mmol) in DCM was added 4M HCl indioxane (0.7 mL, 2.9 mmol). The reaction mixture was stirred at roomtemperature for 0.5 hours. Upon complete removal of the Boc protectinggroup, the reaction was concentrated in vacuo to give the title compound33E as a mixture of atropisomers.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(33F)

To a solution of 33E (70 mg) in DMA (3 mL) was added triethylamine(0.046 mL, 0.32 mmol), followed by2-((3bS,4aR)-3-(trifluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (31 mg, 0.1 mmol) and HATU (46 mg, 0.12 mmol). After stirring for30 minutes, the reaction mixture was filtered and purified by reversephase HPLC to provide the product 33F as a mixture of atropisomers. ¹HNMR (400 MHz, cd₃od) δ 7.83 (dd), 7.72-7.64 (m), 7.50-7.55 (m),7.32-7.07 (m), 6.78-6.70 (m), 6.52-6.48 (m), 6.33-6.31 (m), 5.35-5.28(m), 5.05-4.37 (m), 3.56 (s), 3.21-3.09 (m), 3.00-2.90 (m), 2.54-2.40(m), 1.64 (s), 1.50-1.39 (m), 1.10-0.88 (m). MS (m/z) 804.1 [M+H]⁺.

Example 34

Synthesis ofN—((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamide(34)

The title compound (34) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing 37A and2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid (WO2013006738). ¹H NMR (400 MHz, cd₃od) δ 7.91-7.86 (m), 7.71 (dd),7.54 (dd), 7.22-7.17 (m), 6.87-6.69 (m), 6.66-6.56 (m), 6.41-6.30 (m),5.35-5.25 (m), 5.08-4.97 (m), 4.90-4.71 (m), 4.36-4.29 (m), 3.76-3.66(m), 3.65-3.57 (m), 3.18-3.13 (m), 3.07 (dt), 3.01-2.90 (m), 2.75-2.64(m), 2.21-2.04 (m), 1.76-1.61 (m), 1.10-1.03 (m), 1.00-0.90 (m),0.75-0.70 (m), 0.69-0.62 (m). MS (m/z) 686.2 [M+H]⁺.

Example 35

Synthesis of 6-bromo-N-(oxetan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide(35B)

6-bromoimidazo[1,2-a]pyridine-8-carboxylic acid hydrochloride (235 mg,0.85 mmol) and HATU (386.16 mg, 1.02 mmol) were combined in DMF (4 ml)and treated with iPr₂NEt (0.37 ml, 2.12 mmol). 3-Oxetamine hydrochloride(92.31 mg, 0.85 mmol) was added and the reaction stirred at ambienttemperature for 1 h. Water (2 ml) was added and a solid precipitated.The solids were collected by filtration to provide the desired product.MS (m/z) 296.0 [M+H]⁺.

Synthesis of (8-(oxetan-3-ylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)boronicacid (35C)

The title compound (35C) was prepared according to the method presentedfor the synthesis of 27D in Example 27 utilizing 35B wherein the boronicester hydrolyzed and the corresponding boronic acid was isolated. MS(m/z) 262.1 [M+H]⁺.

Synthesis of6-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-N-(oxetan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide(35D)

The title compound (35D) was prepared according to the method presentedfor the synthesis of 27G in Example 27 utilizing 14B and 35C. ¹H NMR(400 MHz, Methanol-d₄) δ 9.15 (d), 8.80 (d), 8.27 (d), 8.11 (d),7.84-7.69 (m), 7.65 (dd), 7.53 (dd), 6.89-6.64 (m), 6.53-6.37 (m),5.34-5.13 (m), 4.73-4.49 (m), 4.49-4.34 (m), 3.96-3.58 (m), 3.25-3.03(m), 2.59-2.36 (m), 1.51-1.29 (m), 1.18-0.95 (m). MS (m/z) 796.2 [M+H]⁺.

Example 36

Synthesis of (4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (36B)

In a microwave vessel, 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (100mg, 0.47 mmol) was combined with bis(pinacolato)diboron (177 mg, 0.7mmol), KOAc (91 mg, 0.93 mmol), and PdCl₂(PCy₃)₂ (34 mg) in dioxane (4.5ml). Argon was bubbled into the reaction solution for 15 min. Thereaction was heated in a microwave reactor at 155° C. for 15 min. Aftercooling to ambient temperature, the reaction was partitioned betweenEtOAc and water. The organics were separated, dried, and removed invacuo to provide the title compound. MS (m/z) 181.1 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(36C)

The title compound (36C) was prepared according to the method presentedfor the synthesis of 27G in Example 27 utilizing 14B and 36B. ¹H NMR(400 MHz, Methanol-d₄) δ 8.71 (s), 7.63 (s), 7.53-7.42 (m), 6.64 (s),6.57 (s), 6.32 (s), 3.14-2.97 (m), 2.56-2.40 (m), 1.62 (s), 1.42-1.34(m), 1.16-1.04 (m). MS (m/z) 715.1 [M+H]⁺.

Example 37

Synthesis of1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(37A)

The title compound (37A) was prepared according to the method presentedfor the synthesis of compound 39B of Example 39 utilizing 33A. MS (m/z)274.2 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(37B)

To compound 21E (310 mg, 0.78 mmol) in dichloromethane (3 ml) was addedtriethylamine (217 μL, 1.56 mmol) and di-tert-butyldicarbonate (170 mg,0.78 mmol). The mixture was stirred for one hour at ambient temperaturethen concentrated in vacuo.

The residue was purified by silica gel chromatography to afford thetitle compound (37B). MS (m/z) 459.86 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(5-(3-amino-1-methyl-1H-indazol-7-yl)-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(37C)

The title compound (37C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 21G ofExample 21 utilizing compound 37B and 37A. MS (m/z) 526.81 [M+H]⁺.

Synthesis of(S)-7-(4-(1-amino-2-(3,5-difluorophenyl)ethyl)-2-(methylthio)pyrimidin-5-yl)-1-methyl-1H-indazol-3-aminehydrochloride (37D)

Compound 37C (78 mg, 0.15 mmol) was dissolved in 2 mL of 1,4-dioxane andcooled to 0° C. To it was added 4N HCl/1,4-dioxane (2 mL). The reactionmixture was stirred at room temperature for 7 hours. The solvent wasremoved and dried to afford the title compound 37D as a mixture ofatropisomers. MS (m/z) 427.01 [M+H]⁺.

Synthesis of(S)—N-(1-(5-(3-amino-1-methyl-1H-indazol-7-yl)-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(37E)

A mixture of2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (44 mg, 0.14 mmol), compound 37D (69 mg, 0.15 mmol) and HATU (68mg, 0.18 mmol) in 1.5 mL of DMF was cooled to 0° C. To it was addedN,N-diisopropylethylamine (0.1 mL, 0.6 mmol). The reaction mixture wasallowed to stir at 0° C. for 5 minutes then partitioned between EtOAcand 5% aqueous LiCl solution. The organic layer was separated, washedwith brine and concentrated. The residue was purified by reverse phaseHPLC) to afford the title product 37E as a mixture of atropisomers. MS(m/z) 710.95 [M+H]⁺.

Synthesis of(S)—N-(1-(5-(3-amino-1-methyl-1H-indazol-7-yl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(37F)

The title compound (37F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 21H ofExample 21 utilizing compound 37E and 2-methylbut-3-yn-2-ol. ¹H NMR (400MHz, Methanol-d₄) δ 9.01 (d), 8.69 (d), 7.88-7.78 (m), 7.70-7.41 (m),7.40-7.28 (m), 7.10 (dt), 6.96-6.52 (m), 6.35 (d), 5.41-5.23 (m),5.15-5.05 (m), 5.04-4.91 (m), 3.45-3.47 (m), 3.20 (s), 3.13-2.83 (m),2.62-2.35 (m), 1.62 (s). MS (m/z) 747.03 [M+H]+.

Example 38

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)acetamide(38)

The title compound (38) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 27G in Example 27utilizing 27F and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. HPLC retention time 6.48 min and 6.58 min corresponding to eachatropisomer (2-98% acetonitrile:water with 0.1% trifluoroacetic acid,8.5 min gradient on a Phenomonex Kinetex C18 column 4.6×100 mm). MS(m/z) 710.1 [M+H]⁺.

Example 39

Synthesis ofN-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazol-3-yl)methanesulfonamide(39B)

To 39A (prepared similarly to 33B of example 33 utilizing7-bromobenzo[d]isoxazol-3-amine instead of7-bromo-1-methyl-1H-indazol-3-amine) (87 mg, 0.3 mmol) in dioxane (3 mL)was added bis(pinacolato)diboron (107 mg, 0.4 mmol), and PdCl₂[P(Ph)₃]₂(21 mg, 0.03 mmol). The reaction mixture sealed and heated to 100° C.for 16 h. The reaction was cooled to room temperature and telescoped tothe next reaction. MS (m/z) 260.2 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-(methylsulfonamido)benzo[d]isoxazol-7-yl)pyridin-2-yl)ethyl)acetamide(39C)

The title compound (39C) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing 39B and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. MS (m/z) 791.1 [M+H]⁺. HPLC retention time 7.25 min (2-98%acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on aPhenomonex Kinetex C18 column).

Example 40

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyrimidin-4-yl)ethyl)acetamide(40)

The title compound (40) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 37F ofExample 37 utilizing compound 37B andN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(compound 33C). ¹H NMR (400 MHz, Methanol-d₄): δ 8.73 (d), 7.90 (ddd),7.48-7.40 (m), 7.25 (dd), 7.18 (dd), 7.04-6.53 (m), 6.44-6.25 (m),5.42-5.38 (m), 5.09-4.88 (m), 3.41 (s), 3.19 (s), 3.14-2.90 (m),2.63-2.20 (m), 1.64 (d). MS (m/z) 824.90 [M+H]⁺

Example 41

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyrimidin-4-yl)ethyl)acetamide(41)

The title compound (41) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 23B ofExample 23 utilizing compound 22A andN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(33C). ¹H NMR (400 MHz, Methanol-d₄) δ 9.12-8.90 (m), 8.73 (dd), 7.90(dd), 7.42 (d), 7.24 (t), 7.17 (t), 6.87-6.68 (m), 6.61 (t), 6.37 (dd),5.47-5.35 (m), 5.02 (q), 4.85-4.46 (m), 3.40 (d), 3.19 (d), 3.12 (dd),3.07-2.83 (m), 2.62-2.33 (m) 1.64 (d), 1.48-1.31 (m), 1.16-0.95 (m). MS(m/z) 804.85 [M+H]⁺.

Example 42

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(42)

The title compound (42) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.80 (d), 7.82 (d), 7.75-7.69 (m),7.59-7.51 (m), 7.40-7.20 (m), 7.19-7.05 (m), 6.80 (d), 6.60-6.52 (m),6.30 (d), 5.08-4.97 (m), 4.90-4.71 (m), 3.34 (s), 3.25-3.00 (m),2.90-2.75 (m), 2.76-2.64 (m), 2.25-2.00 (m, 5H), 1.64 (s). MS (m/z)824.2 [M+H]⁺.

Example 43

Synthesis of2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(43)

The title compound (43) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing 20C and2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 7.80 (d), 7.45 (d), 7.51 (d), 7.25-7.20(m, 1H), 6.80-6.52 (m), 6.45 (d), 5.35-5.25 (m), 5.08-4.97 (m),4.90-4.71 (m), 3.34 (s), 3.25-3.02 (m), 2.98-2.64 (m), 2.75-2.35 (m),2.25-2.00 (m), 1.80-1.70 (m), 1.64 (d), 1.00-0.90 (m), 0.65-0.58 (m). MS(m/z) 764.2 [M+H]⁺.

Example 44

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(44)

To a stirred solution of 25-(31 mg, 0.04 mmol) and pyridine (0.024 mL,0.03 mmol) in dichloroethane (0.5 mL) was added a solution of sulfamoylchloride (12 mg, 0.1 mmol) in dichloroethane (˜0.2 mL). The reaction washeated at 60° C. for 1 h. Upon cooling, the reaction mixture wasconcentrated in vacuo, diluted with EtOAc and washed with water then 1 MHCl. The organic layer was dried over Na₂SO₄, filtered, concentrated invacuo, and purified by reverse phase HPLC to provide the title compound44 as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ 8.86-6.25 (m,8H), 5.38-4.97 (m, 1H), 4.85-4.73 (m, 2H), 3.26-3.06 (m, 1H), 3.04-2.90(m, 2H), 2.63-2.37 (m, 2H), 1.69-1.56 (m, 6H), 1.52-1.32 (m, 1H),1.19-0.98 (m, 1H). MS (m/z) 805.1 [M+H]⁺.

Example 45

Synthesis of 2-(7-bromo-1H-indazol-3-yl)isoindoline-1,3-dione (45B)

To 7-bromo-1H-indazol-3-amine (45A, 1.2 g, 5.5 mmol) in toluene (30 mL)was added phthalic acid (990 mg, 6.0 mmol). The flask was fitted with aDean-Stark trap and the reaction mixture was stirred for 12 hours at180° C. The reaction was allowed to cool, the solids were filtered offand used with no further purification to provide the title compound. MS(m/z) 343.1 [M+H]⁺.

Synthesis of 7-bromo-1-ethyl-1H-indazol-3-amine (45C)

To 45B (100 mg, 0.3 mmol) in DMF (2 mL) was added Cs₂CO₃ (95.2 mg, 0.3mmol) and iodoethane (0.028 ml, 0.35 mmol). The reaction mixture wasstirred for 10 minutes. The reaction mixture was diluted with EtOAc andbrine, extracted 2× with EtOAc, organic layer dried over sodium sulfate,and concentrated. To the crude mixture was added EtOH (2 ml) andhydrazine hydrate (1 ml) the reaction mixture was stirred for 30minutes. The mixture was concentrated and purified by flash columnchromatography to provide the title compound. MS (m/z) 240.1 [M+H]⁺.

Synthesis of1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(45D)

To 45C (80 mg, 0.3 mmol) in dioxane (5 mL) was addedbis(pinacolato)diboron (84.6 mg, 0.3 mmol), potassium acetate (32.7 mg,0.3 mmol), and Pd(PCy₃)₂Cl₂ (12.3 mg, 0.02 mmol). The reaction mixturewas heated in the microwave for 30 minutes at 150° C. The reaction wascooled and the solids were filtered off. The mixture was concentratedand purified by flash column chromatography to provide the titlecompound. MS (m/z) 288.2 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-1-ethyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(45E)

To 45D (40 mg, 0.1 mmol) in dioxane (4 mL) and MeOH (0.75 ml) was added14B (69 mg, 0.1 mmol), 2M K₂CO₃ (0.4 ml), LiCl (17.7 mg, 0.4 mmol) andPd(PPh₃)₂Cl₂ (4.9 mg, 0.007 mmol). The reaction mixture was heated inthe microwave for 30 minutes at 150° C. The reaction was cooled, dilutedwith EtOAc and brine, and extracted 2× EtOAc. The organic layer wasdried over sodium sulfate, concentrated and purified by flash columnchromatography to provide the title compound as a mixture ofatropisomers. MS (m/z) 576.0 [M+H]⁺.

Synthesis of(S)-4-(5-(3-amino-1-ethyl-1H-indazol-7-yl)-6-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(45F)

The title compound (45F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 45E. MS (m/z) 476.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-1-ethyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(45G)

The title compound (45G) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 45F and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR ¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (d), 7.87-7.75 (m),7.71 (d), 7.59-7.50 (m), 7.26-7.19 (m), 7.18-7.12 (m), 7.12-7.04 (m),6.76-6.63 (m), 6.60 (d), 6.47-6.41 (m), 6.27 (d), 5.11-5.01 (m), 4.81(d), 4.72 (d), 3.67-3.55 (m), 3.51-3.43 (m), 3.39-3.24 (m), 3.15-3.10(m), 3.09-2.84 (m), 2.56-2.40 (m), 1.64 (s), 1.45-1.33 (m), 1.31-1.25(m), 1.14-1.03 (m), 0.87 (dt). MS (m/z) 740.2 [M+H]⁺.

Example 46

Synthesis ofN—((S)-1-(3-(3-amino-1H-indazol-5-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(46)

The title compound (46) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.99 (d), 7.62-7.54 (m), 7.51-7.40 (m),7.33 (d), 6.72-6.62 (m), 6.29-6.22 (m), 5.53-5.43 (m), 4.92 (d), 3.03(d), 2.60-2.45 (m), 1.63 (s), 1.48-1.37 (m), 1.16-1.04 (m). MS (m/z)712.1 [M+H]⁺.

Example 47

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(1-methyl-1H-imidazole-4-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(47)

To a solution ofN—((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(25, 10 mg, 0.014 mmol) in dichloromethane (0.2 mL) was added pyridine(6.6 μL, 0.083 mmol), followed by 1-methyl-1H-imidazole-4-sulfonylchloride (3.7 mg, 0.021 mmol). After stirring for 1 h, the reactionmixture was concentrated and purified by reverse phase HPLC to providethe title product as a mixture of atropisomers. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (dd), 7.71-7.63 (m), 7.57-7.48 (m), 7.30 (s),7.14-7.03 (m), 6.79-6.70 (m), 6.66-6.55 (m), 6.38-6.26 (m), 5.25 (dd),4.96 (dd), 4.87-4.72 (m), 3.67 (s), 3.46 (s), 3.27 (s), 3.25-3.18 (m),3.09-3.02 (m), 3.00-2.87 (m), 2.58-2.43 (m), 1.64 (s), 1.64 (s),1.50-1.37 (m), 1.16-1.06 (m). MS (m/z) 870.10 [M+H]⁺.

Example 48

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(1-methyl-1H-pyrazole-4-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(48)

The title compound (48) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (47) ofExample 47 utilizing 1-methyl-1H-pyrazole-4-sulfonyl chloride. ¹H NMR(400 MHz, Methanol-d₄) δ 7.95 (s), 7.77-7.66 (m), 7.61 (s), 7.57-7.48(m), 7.24-7.18 (m), 7.17-7.10 (m), 7.07 (dd), 6.78-6.68 (m), 6.63 (dd),6.60-6.50 (m), 6.40-6.26 (m), 5.26 (dd), 5.02 (dd), 4.88-4.71 (m), 3.83(s), 3.60 (s), 3.29 (s), 3.27-3.21 (m), 3.09-3.01 (m), 3.00-2.87 (m),2.58-2.39 (m), 1.64 (s), 1.49-1.36 (m), 1.16-1.04 (m). MS (m/z) 870.03[M+H]⁺.

Example 49

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(1H-pyrazole-4-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(49)

The title compound (49) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (47) ofExample 47 utilizing 1H-pyrazole-4-sulfonyl chloride. ¹H NMR (400 MHz,Methanol-d₄) δ 8.74 (d), 8.60 (q), 7.91 (s), 7.83 (s), 7.76-7.63 (m),7.57-7.47 (m), 7.21 (dd), 7.13 (dd), 7.03 (dd), 6.79-6.68 (m), 6.61-6.50(m), 6.46 (dd), 6.38-6.25 (m), 5.34-5.22 (m), 5.05-4.94 (m), 4.87-4.78(m), 3.28 (s), 3.26-3.16 (m), 3.15-3.07 (m), 3.00-2.90 (m), 2.58-2.43(m), 1.64 (s), 1.64-1.64 (m), 1.49-1.37 (m), 1.17-1.07 (m). MS (m/z)856.03 [M+H]⁺.

Example 50

Synthesis ofN—((S)-1-(3-(3-(3-cyclopropylureido)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(50)

To a solution ofN—((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(25, 10 mg, 0.014 mmol) and DIPEA (3.5 μL, 0.021 mmol) indichloromethane (0.1 mL) was added triphosgene (4.5 mg, 0.015 mmol).After stirring for 1 minute cyclopropylamine (3.5 μL, 0.055 mmol) wasadded. After stirring for 15 minutes, the reaction mixture wasconcentrated and purified by reverse phase HPLC to provide the titleproduct as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ7.87 (m), 7.68 (dd), 7.53 (dd), 7.23 (dd), 7.13 (dd), 7.02 (dd),6.77-6.68 (m), 6.63-6.54 (m), 6.49 (dd), 6.38-6.32 (m), 6.32-6.25 (m),5.25 (dd), 5.01 (t), 4.79 (t), 3.26 (s), 3.25-3.19 (m), 3.14-3.04 (m),3.00-2.89 (m), 2.73-2.64 (m), 2.56-2.41 (m), 1.64 (s), 1.64 (s),1.49-1.36 (m), 1.17-1.04 (m), 0.81-0.71 (m), 0.61-0.51 (m). MS (m/z)809.12 [M+H]⁺.

Example 51

Synthesis ofN-(7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-4-methylpiperazine-1-carboxamide(51)

The title compound (51) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (50) ofExample 50 utilizing 1-methylpiperazine. ¹H NMR (400 MHz, Methanol-d₄) δ7.79-7.66 (m), 7.54 (dd), 7.23 (dd), 7.16 (dd), 7.09 (dd), 6.78-6.68(m), 6.66-6.57 (m), 6.43-6.36 (m), 6.36-6.28 (m), 5.29 (dd), 5.02 (dd),4.85-4.71 (m), 4.39 (s), 3.67-3.45 (m), 3.27-3.22 (m), 3.14-3.06 (m),3.03-2.89 (m), 2.58-2.41 (m), 1.65 (s), 1.64 (s), 1.49-1.36 (m),1.17-1.10 (m), 1.10-1.04 (m). MS (m/z) 852.11 [M+H]⁺.

Example 52

Synthesis ofN-(7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)morpholine-4-carboxamide(52)

The title compound (52) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (50) ofExample 50 utilizing morpholine. ¹H NMR (400 MHz, Methanol-d₄) δ7.77-7.66 (m), 7.54 (dd), 7.22 (dd), 7.15 (dd), 7.08 (dd), 6.77-6.69(m), 6.66-6.60 (m), 6.58 (dd), 6.42-6.36 (m), 6.36-6.29 (m), 5.32 (dd),5.03 (dd), 4.85-4.79 (m), 4.79-4.71 (m), 3.74 (dd), 3.61-3.53 (m),3.27-3.20 (m), 3.15-3.07 (m), 3.02 (s), 3.00-2.90 (m), 2.58-2.41 (m),1.65 (s), 1.64 (s), 1.49-1.35 (m), 1.16-1.10 (m), 1.10-1.04 (m). MS(m/z) 839.13 [M+H]⁺.

Example 53

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(3-((N-ethylsulfamoyl)amino)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(53)

The title compound (53) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (44) ofExample 44 utilizing ethyl sulfamoylchloride. ¹H NMR (400 MHz,Methanol-d₄) δ 8.84-8.74 (m), 7.95-7.85 (m), 7.69 (dd), 7.54 (dd), 7.23(dd), 7.15 (dd), 7.09 (dd), 6.79-6.69 (m), 6.66-6.56 (m), 6.39-6.34 (m),6.34-6.26 (m), 5.35-5.25 (m), 5.07-4.98 (m), 4.86-4.71 (m), 3.23 (m),3.15-3.02 (m), 3.00 (s), 2.98-2.88 (m), 2.58-2.40 (m), 1.65 (s), 1.64(s), 1.49-1.36 (m), 1.12 (t), 1.10-1.02 (m). MS (m/z) 833.14 [M+H]⁺.

Example 54

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(54)

The title compound (54) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 44 ofExample 44 utilizing and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.75 (d), 8.01-7.93 (m), 7.72-7.63 (m),7.53 (dd), 7.28-7.05 (m), 6.87-6.51 (m), 6.34 (m), 5.35-5.25 (m),5.07-4.96 (m), 4.80-4.65 (m), 3.33 (s), 3.24-2.88 (m), 2.53-2.38 (m),1.64 (d), 1.45-1.32 (m), 1.13-0.99 (m). MS (m/z) 787.1 [M+H]⁺.

Example 55

Synthesis of (S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(55A)

To 19C (1.5 g, 4.8 mmol) in dioxane (100 mL) was added 14B (1.6 g, 3.2mmol), 1N sodium bicarbonate (8.4 ml, 8.4 mmol), and PdCl₂(PCy₃)₂ (238mg, 0.3 mmol). The reaction mixture was stirred for 30 minutes at 125°C. The reaction was cooled, diluted with EtOAc and brine. The mixturewas extracted 2× with EtOAc, the organic layer was dried over sodiumsulfate, was concentrated and purified by flash column chromatography toprovide the title compound as a mixture of atropisomers. MS (m/z) 596.7[M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(55B)

The title compound (55B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 55A. MS (m/z) 496.5 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(55C)

The title compound (55C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 55B and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.83-8.69 (m), 7.65 (d), 7.53 (d),7.13-7.06 (m), 7.07-6.99 (m), 6.96 (d), 6.81-6.71 (m), 6.67-6.56 (m),6.48-6.39 (m), 6.41-6.30 (m), 5.30-5.19 (m), 5.07-4.96 (m), 4.83-4.71(m), 3.27-3.22 (m), 3.17 (s), 3.10 (s), 3.04-2.91 (m), 2.81 (s),2.61-2.39 (m), 1.63 (s), 1.49-1.37 (m), 1.37-1.24 (m), 1.23-1.00 (m). MS(m/z) 760.3 [M+H]⁺.

Example 56

Synthesis of 2,5-dioxopyrrolidin-1-yl2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(56A)

To a stirring solution of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (1.00 g, 3.54 mmol), N-hydroxysuccinimide (0.61 g, 5.32 mmol), andpyridine (0.968 mL, 12.1 mmol) was added dropwise at −5° C. thionylchloride (0.439 mL, 6.02 mmol). After stirring at −5° C. for 20 min,2.0M aqueous NaCl (10 mL) was added and the product was extracted withtwo portions of ethyl acetate (12 mL). The combined organic layers weredried over Na₂SO₄, filtered, concentrated in vacuo, and purified bysilica gel column chromatography to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ 5.88-5.63 (m, 4H), 2.77-2.55 (m, 2H), 1.56-1.31 (m, 2H),1.12-0.98 (m, 2H).

Synthesis ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-4-methylpiperazine-1-sulfonamide(56B)

To a stirring solution of 7-bromo-1-methyl-1H-indazol-3-amine (33A, 250mg, 1.11 mmol) and DABCO (310 mg, 2.77 mmol) in acetonitrile was added4-methylpiperazine-1-sulfonyl chloride HCl (650 mg, 2.77 mmol). Afterstirring at 50° C. for 3 h, the reaction was concentrated, diluted withwater and extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, filtered, concentrated in vacuo, and purified by silica gelcolumn chromatography to give the title compound. MS (m/z) 387.97[M+H]⁺.

Synthesis of4-methyl-N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)piperazine-1-sulfonamide(56C)

The title compound (56C) was prepared according to the method presentedfor the synthesis of compound (19D) of Example 19 utilizingN-(7-bromo-1-methyl-1H-indazol-3-yl)-4-methylpiperazine-1-sulfonamide(56B). MS (m/z) 436.18 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(4-methylpiperazine-1-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(56D)

The title compound (56D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (19E) ofExample 19 utilizing4-methyl-N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)piperazine-1-sulfonamide(56C).

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-4-methylpiperazine-1-sulfonamide(56E)

The title compound (56E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (14C) ofExample 14 utilizing (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(4-methylpiperazine-1-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(56D). The resulting crude product was basified to pH ˜8 with 1M aqueousNaHCO₃ and extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, filtered, concentrated in vacuo, and taken to the next stepwithout further purification.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(4-methylpiperazine-1-sulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(56F)

To a solution of crude(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-4-methylpiperazine-1-sulfonamide(56E, 62.9 mg, 0.101 mmol assuming 100% purity) and DIPEA (17.5 μL,0.101 mmol) in acetonitrile (2 mL) was 2,5-dioxopyrrolidin-1-yl2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(56A, 38.3 mg, 0.101 mmol). After stirring for 1 h, the reaction mixturewas filtered and purified by reverse phase HPLC to provide the titleproduct as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ8.01 (dd), 7.87-7.77 (m), 7.73-7.52 (m), 7.28-7.15 (m), 6.95 (dd),6.76-6.61 (m), 6.46-6.41 (m), 6.19-6.11 (m), 5.24 (dd), 5.03-4.90 (m),4.78 (d), 3.91-3.67 (m), 3.36 (s), 3.13 (dq), 3.00 (s), 2.94-2.87 (m),2.75 (dd), 2.70 (s), 2.60-2.45 (m), 1.65 (s), 1.64 (s), 1.49-1.38 (m),1.15-0.94 (m). MS (m/z) 888.35 [M+H]⁺.

Example 57

Synthesis ofN—((S)-1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(57)

The title compound (57) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 55B and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Chloroform-d) δ 8.02 (s), 7.54-7.37 (m), 7.10(d), 7.07-6.99 (m), 6.75 (d), 6.72 (t), 6.67-6.56 (m), 6.51-6.44 (m),6.25-6.13 (m), 6.02 (d), 5.56 (q), 5.01 (td), 4.75-4.69 (m), 3.08 (s),2.98-2.86 (m), 2.80 (s), 2.55-2.39 (m), 1.71 (s), 1.42 (q), 1.22-1.14(m). MS (m/z) 742.8 [M+H]⁺.

Example 58

Synthesis of 7-bromo-4-iodo-1-methyl-1H-indazol-3-amine (58B)

The title compound (58B) was prepared according to the method presentedfor the synthesis of compound 19B of Example 19 utilizing 58A. MS (m/z)352.4 [M+H]⁺.

Synthesis of 7-bromo-1,4-dimethyl-1H-indazol-3-amine (58C)

To 58B (3.0 g, 8.5 mmol) in dioxane (10 mL) and DMF (10 ml) was addedTrimethylboroxine (4.8 ml, 34.1 mmol), 2M K₂CO₃ in water (8.5 ml), andPd(PPh₃)₂Cl₂ (600 mg, 0.8 mmol). The reaction mixture was stirred for 5hours at 160° C. The reaction was cooled, diluted with EtOAc and brine.The mixture was extracted 2× with EtOAc, the organic layer was driedover sodium sulfate, concentrated and purified by flash columnchromatography to provide the title compound. MS (m/z) 240.1 [M+H]⁺.

Synthesis of1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(58D)

The title compound (58D) was prepared according to the method presentedfor the synthesis of compound 19C of Example 19 utilizing 58C. MS (m/z)288.2 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-1,4-dimethyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(58E)

The title compound (58E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing 58D. MS (m/z) 576.2 [M+H]⁺.

Synthesis of(S)-4-(5-(3-amino-1,4-dimethyl-1H-indazol-7-yl)-6-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(58F)

The title compound (58F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 58E. MS (m/z) 476.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-1,4-dimethyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(58G)

The title compound (58G) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 58F and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Methanol-d₄) δ: 8.68-8.57 (m), 7.69-7.45 (m), 7.06 (d),6.85 (d), 6.80 (d), 6.76-6.66 (m), 6.66-6.53 (m), 6.45 (d), 6.38 (d),6.31 (d), 5.26 (s), 5.08-4.98 (m), 4.73 (d), 3.27-3.19 (m), 3.16 (s),3.06 (dd), 2.91 (dd), 2.84 (s), 2.74-2.66 (m), 2.53-2.38 (m), 1.64 (d),1.43-1.24 (m), 1.12-0.98 (m). MS (m/z) 722.2 [M+H]⁺.

Example 59

Synthesis of (R)-tert-butyl4-((5-bromo-6-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-2-yl)ethynyl)-2,2-dimethyloxazolidine-3-carboxylate(59A)

The title compound was prepared similarly to compound 14D in example 14utilizing (R)-tert-butyl 4-ethynyl-2,2-dimethyloxazolidine-3-carboxylateinstead of 2-methylbut-3-yn-2-ol. MS (m/z) 799 [M−H]—.

Synthesis ofN—((S)-1-(6-((R)-3-amino-4-hydroxybut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(59B)

To a solution of 59A (110 mg, 0.13 mmol) in dioxane (3 mL) was added 20C(67 mg, 0.19 mmol), sodium bicarbonate (1M, 0.41 mL) followed byPdCl₂[P(Ph)₃]₂ (4.8 mg, 0.06 mmol). The reaction was sealed and heatedin a microwave reactor for 20 min at 150° C. Upon cooling, the reactionmixture was first diluted with EtOAc and washed with brine (2×10 mL),dried over Na₂SO₄, filtered and concentrated. The crude materialpurified by reverse phase HPLC. Fractions containing the product werepooled and treated with neat TFA to give the title compound 59B as amixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ 7.89-7.73 (m),7.69-7.60 (m), 7.32-7.27 (m), 7.25-7.15 (m), 7.10-7.07 (m), 6.80-6.70(m), 6.69-6.47 (m), 6.50 (d), 6.40-6.28 (m), 5.32-5.25 (m), 5.05-4.96(m), 4.80-4.72 (d), 4.52-4.44 (m), 4.09-3.98 (m), 3.94-3.84 (m),3.21-3.08 (m), 3.05-2.89 (m), 2.59-2.37 (m), 1.46-1.35 (m), 1.11 (s),1.04 (s). MS (m/z) 805.1 [M+H]⁺.

Example 60

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(1-methyl-1H-pyrazol-4-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(60)

In a microwave tube were charged with compound 61A (20 mg, 0.026 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11mg, 0.053 mmol) and PdCl₂[PPh₃]₂ (2 mg, 0.003 mmol). To the mixture wasadded 0.5 mL of 1,4-dioxane and 0.1 mL of sodium bicarbonate aqueoussolution (1M). The mixture was heated to 120° C. for 4 minutes in amicrowave synthesizer. After cooled to room temperature, it waspartitioned between EtOAc and water. The organic layer was separated andwashed with brine, then dried over MgSO₄, filtered and concentrated. Theresidue was purified by reverse phase HPLC to afford the title compound60 as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ8.43-8.29 (m), 8.28-8.09 (m), 7.91-7.72 (m), 7.76-7.58 (m), 7.15-7.00(m), 6.82-6.68 (m), 6.53 (dd), 6.36-6.14 (m), 5.39-5.18 (m), 5.08-4.91(m), 4.84 (d), 4.02 (d), 3.38 (s), 3.23-3.14 (m), 3.14 (s), 3.01 (d),2.93 (dd), 2.63-2.30 (m), 1.50-1.26 (m), 1.17-0.79 (m). MS (m/z): 802.16[M+H]⁺

Example 61

Synthesis ofN—((S)-1-(6-chloro-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(61A)

The title compound (61A) was prepared according to the method presentedfor the synthesis of compound 157F of Example 157 utilizingN-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(33C) instead of 19D. MS (m/z) 756.1 [M+H]⁺.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-(dimethylamino)prop-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(61B)

To the reaction vial containing 61A (20 mg, 0.026 mmol) in DMF (0.2 mL)was added N,N-dimethylprop-2-yn-1-amine (11 mg, 0.13 mmol),PdCl₂[P(Ph)₃]₂ (1.87 mg, 0.003 mmol), and diethylamine (0.02 mL, 0.26mmol). The reaction mixture was flushed with argon gas for 5 min thensealed and heated in a microwave reactor to 125° C. for 15 min. Uponcooling, the reaction mixture was filtered and purified by reverse phaseHPLC to provide the title product as a mixture of atropisomers. ¹H NMR δ8.70 (m), 7.90-7.76 (m), 7.70 (d), 7.16 (m), 6.75 (tt), 6.57 (dd),6.41-6.28 (m), 5.35-5.25 (m), 5.08-4.97 (m), 4.82-4.68 (m), 4.47 (d),3.30-3.06 (m), 3.05-2.88 (m), 2.54-2.43 (m), 1.48-1.35 (m), 1.15-1.11(m), 1.09-1.00 (m). MS (m/z) 803.2 [M+H]⁺.

Example 62

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((1S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3,4-dimethylpent-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(62)

The title compound (62) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 61 ofExample 61 utilizing 3,4-dimethylpent-1-yn-3-ol. ¹H NMR (400 MHz, cd₃od)δ 8.73 (m), 7.83-7.79 (m), 7.75-7.70 (m), 7.60-7.54 (m), 7.277.12 (m),7.05 (t), 6.65 (t), 6.61 (t), 6.52 (t), 6.35-6.21 (m), 5.35-5.21 (m),5.06-4.97 (m), 4.85-4.70 (m), 3.34 (s), 3.20-3.08 (m), 3.01-2.88 (m),2.56-2.38 (m), 2.01-1.89 (m), 1.60-1.54 (d), 1.46-1.34 (m), 1.21-1.09(m), 1.08-1.03 (m). MS (m/z) 832.1 [M+H]⁺.

Example 63

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(63)

The title compound (63) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 61 ofExample 61 utilizing 2,2-dimethylbut-3-yn-1-ol. ¹H NMR (400 MHz, cd₃od)δ 8.65 (d), 7.83 (m), 7.66 (dd), 7.51 (dd), 7.08 (dd), 6.73 (tt), 6.50(dt), 6.38-6.26 (m), 5.35-5.25 (m), 4.98 (t), 4.85-4.71 (m), 3.57 (s),3.33 (s), 3.15 (d), 3.04-2.87 (m), 2.54-2.43 (m), 1.36 (s), 1.12-1.02(m). MS (m/z) 818.2 [M+H]⁺.

Example 64

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((1S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-4-methylpent-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(64)

The title compound (64) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 61 ofExample 61 utilizing 4-methylpent-1-yn-3-ol. ¹H NMR (400 MHz, cd₃od) δ8.74 (d), 8.67 (d), 7.88-7.79 (m), 7.75-7.66 (m), 7.60-7.50 (m),7.14-7.05 (m), 6.78-6.68 (m), 6.53 (ddt), 6.41-6.29 (m), 5.31-5.25 (m),5.06-4.95 (m), 4.78 (d), 4.45-4.38 (m), 3.34 (s), 3.15 (d), 3.03-2.88(m), 2.55-2.43 (m), 2.06-1.91 (m), 1.39 (q), 1.18-1.10 (m), 1.07 (d). MS(m/z) 818.1 [M+H]+.

Example 65

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(1-methyl-3-(1-methyl-1H-imidazole-4-sulfonamido)-1H-indazol-7-yl)-6-vinylpyridin-2-yl)ethyl)acetamide(65)

Argon was bubbled through a solution ofN—((S)-1-(6-chloro-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(61A, 100 mg, 0.13 mmol), potassium vinyltrifluoroborate (35.4 mg, 0.26mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II)dichloromethane (10.8 mg, 0.01 mmol), and triethylamine (0.06 ml,0.43 mmol) in EtOH (2.6 ml) for 5 mins. The reaction was heated in amicrowave reactor at 150° C. for 20 mins. The product was solid loadedonto silica and purified by silica gel chromatography followed byre-purification by reverse phase HPLC to provide the title product as amixture of atropisomers. ¹H NMR (400 MHz, Methanol-d4) δ 7.85-7.78 (m),7.67-7.62 (m), 7.55-7.48 (m), 7.24-7.14 (m), 7.11-7.05 (m), 7.04-6.94(m), 6.76-6.67 (m), 6.64-6.56 (m), 6.56-6.34 (m), 6.33-6.24 (m),5.67-5.58 (m), 5.31-5.23 (m), 5.03-4.95 (m), 4.86-4.75 (m), 3.34 (s),3.32-3.28 (m), 3.24-3.09 (m), 3.02-2.85 (m), 2.57-2.41 (m), 1.41 (m),1.35-1.24 (m), 1.17-1.10 (m), 1.10-1.03 (m). MS (m/z) 748.15 [M+H]⁺.

Example 66

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-ethyl-3-hydroxypent-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(66)

The title compound (66) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 61 ofExample 61 utilizing 3-ethylpent-1-yn-3-ol. ¹H NMR (400 MHz, cd₃od) δ7.83 (td), 7.74-7.65 (m), 7.54 (dd), 7.28-7.05 (m), 6.78-6.67 (m), 6.62(s), 6.54 (dd), 6.35 (ddd), 5.00 (t), 5.32-5.25 (m), 4.84-4.70 (m), 3.34(s), 3.15 (d), 3.03-2.88 (m), 2.55-2.42 (m), 1.93-1.73 (m), 1.41 (dq),1.16 (td), 1.10-1.01 (m). MS (m/z) 832.1 [M+H]⁺.

Example 67

Synthesis of 1-(allyloxy)but-3-en-2-ol (67B)

The epoxide 67A (3.5 g, 50 mmol) and allyl alcohol (5.8 g, 100 mmol)were dissolved in DMF (100 mL) in a pressure bottle. After cooled to 0°C., NaH (60% suspension in mineral oil, 2.4 g) was added portionwise,stirred for 20 min under argon. The bottle was sealed and heated at 60°C. overnight. The reaction was cooled to 0° C. in an ice bath, quenchedwith 100 mL 2N HCl. The aqueous layer was extracted 3 times with ether(3×100 mL). The combined ether were washed with 5% LiCl and brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column to yield the title compound67B. ¹H NMR (400 MHz, Chloroform-d) δ 6.00-5.74 (m, 2H), 5.45-5.08 (m,4H), 4.31 (tdd, J=7.0, 3.2, 1.5 Hz, 1H), 4.02 (dt, J=5.7, 1.4 Hz, 2H),3.49 (dd, J=9.7, 3.4 Hz, 1H), 3.32 (dd, J=9.7, 7.9 Hz, 1H), 2.56 (s,1H).

Synthesis of 3,6-dihydro-2H-pyran-3-ol (67C)

The title compound (67C) was prepared according to reference: Angew.Chem. Intl. Ed. 2005, 44, 5306-5310. ¹H NMR data: 1H NMR (400 MHz,Chloroform-d) δ 6.06-5.81 (m, 2H), 4.19-3.99 (m, 2H), 3.98-3.89 (m, 1H),3.86-3.66 (m, 2H), 2.77-2.57 (m, 1H).

Synthesis of 2H-pyran-3(6H)-one (67D)

The title compound (67D) was prepared according to reference: Angew.Chem. Intl. Ed. 2005, 44, 5306-5310.

Synthesis of 3-oxabicyclo[4.1.0]heptan-5-one (67E)

To a suspension of NaH (60% in mineral oil, 0.19 g) in DMSO (20 mL) wasadded trimethylsulfonium iodide (1.75 g, 8 mmol) at room temperature.After stirring for 15 min, a solution of 67D (0.6 g, 6 mmol) in DMSO (5mL) was added. After stirring at room temperature for 5 min, thereaction mixture was diluted with ethyl acetate and washed with 5% LiClaqueous solution. The organic layers were dried over Na₂SO₄, filtered,concentrated in vacuo, and purified by silica gel column chromatographyto give the title compound. ¹H NMR (400 MHz, Chloroform-d) δ 4.22-4.03(m, 2H), 3.80 (s, 1H), 3.76 (d, J=6.0 Hz, 1H), 1.95 (ddd, J=9.8, 7.5,4.7 Hz, 1H), 1.85-1.71 (m, 2H), 1.23 (ddd, J=9.8, 7.1, 4.4 Hz, 1H).

Synthesis of3-(trifluoromethyl)-5,5a,6,6a-tetrahydro-1H-cyclopropa[4,5]pyrano[3,2-c]pyrazole(67F)

A solution of compound 67E (90 mg, 0.8 mmol) and ethyl trifluoroacetate(0.16 g, 1.2 mmol) in ether was cooled to −78° C. LiHMDS (0.18 g, 1mmol) was added in one portion. The resulting mixture was stirred at−78° C. for 2 h. The reaction was poured into 1 N HCl aqueous solutionand the aqueous layer was extracted with ether. The organic layers weredried over Na₂SO₄, filtered, concentrated in vacuo to give the titlecompound which was used without further purification. MS (m/z) 209.06[M+H]⁺.

To a solution of crude from last step in ethanol (20 mL) was addedconcentrated sulfuric acid (0.5 mL) and hydrazine monohydrate (1 mL).The resulting mixture was heated at 90° C. for 5 min. Upon completion ofthe reaction, the volatiles were removed in vacuo to give the titlecompound which was used in the next step. MS (m/z) 205.18 [M+H]⁺.

Synthesis of ethyl2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydro-1H-cyclopropa[4,5]pyrano[3,2-c]pyrazol-1-yl)acetate(67G)

To a solution of compound 67F (100 mg, 0.49 mmol) in DMF (2 mL) wasadded bromoethyl acetate (98 mg, 0.59 mmol) and cesium carbonate (160mg, 0.5 mmol) at 0° C. The reaction was heated at 50° C. overnight. Uponcooling, the mixture was purified by reverse phase HPLC to give thetitle compound. MS (m/z) 291.19 [M+H]⁺.

Synthesis of2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydro-1H-cyclopropa[4,5]pyrano[3,2-c]pyrazol-1-yl)aceticacid (67H)

To a solution of compound 67G (16 mg, 0.055 mmol) in a mixture ofTHF:water:MeOH (1 mL:0.5 mL:0.5 mL) was added solid LiOH monohydrate (7mg, 0.165 mmol) at 0° C. After stirring at room temperature for 10 min,the reaction mixture was poured into EtOAc and the organic was washedwith 2 N HCl. The organic layers were dried over Na₂SO₄, filtered,concentrated in vacuo to give the title compound which was used in thenext step. MS (m/z) 263.04 [M+H]⁺.

Synthesis ofN—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydro-1H-cyclopropa[4,5]pyrano[3,2-c]pyrazol-1-yl)acetamide(67I)

The title compound (67I) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydro-1H-cyclopropa[4,5]pyrano[3,2-c]pyrazol-1-yl)aceticacid (67H) and compound 33E. ¹H NMR (400 MHz, Methanol-d₄) δ 7.93-7.78(m), 7.75-7.65 (m), 7.61-7.45 (m), 7.39-6.98 (m), 6.73 (tq), 6.68-6.56(m), 6.34 (tdd), 5.43-4.93 (m), 4.83-4.71 (m), 4.30-3.97 (m), 3.22-3.00(m), 3.02-2.76 (m), 2.10-1.70 (m), 1.16 (dddd), 0.86-0.64 (m). MS (m/z)784.34 [M+H]⁺.

Example 68

Synthesis ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoroacetamide (68A)

To a solution of 7-bromo-1-methyl-1H-indazol-3-amine (33A, 500 mg, 2.21mmol) and N,N-diisopropylethylamine (0.578 mL, 3.32 mmol) indichloromethane (5 ml) was added dropwise at 0° C. trifluoroaceticanhydride (697 mg, 3.32 mmol). The reaction was warmed to roomtemperature and stirred for 30 min. The reaction mixture was washed withwater. The aqueous layer was back-extracted with dichloromethane. Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedin vacuo, and purified by silica gel column chromatography to give thetitle compound. ¹H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.87 (d,1H), 7.60 (d, 1H), 7.01 (t, 1H), 4.37 (s, 3H).

Synthesis ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoro-N-methylacetamide(68B)

To a stirred solution ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoroacetamide (68A, 100mg, 0.31 mmol) in DMF (0.6 ml) was added potassium t-butoxide (36.6 mg,0.33 mmol). The reaction was sonicated until the solution becamehomogeneous and the reaction was stirred at room temperature for 30mins. To the reaction was added iodomethane (29 μL, 0.47 mmol). Afterstirring for 1 h, the reaction was diluted with ethyl acetate and washedwith water, followed by 0.5M aqueous NaCl. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was used in the next step without further purification.

Synthesis of 7-bromo-N,1-dimethyl-1H-indazol-3-amine (68C)

To a solution ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoro-N-methylacetamide(68B, 104 mg) in methanol (3 ml) was added 8M NaOH (46.6 μl). Afterstirring for 30 mins, the solution was concentrated, extracted withethyl acetate (4 mL) and washed water (4 mL), followed by 2M aqueousNaCl (4 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was used in the next stepwithout further purification. MS (m/z) 240.15 [M+H]⁺.

Synthesis ofN,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(68D)

The title compound (68D) was prepared according to the method presentedfor the synthesis of compound 19C of Example 19 utilizing7-bromo-N,1-dimethyl-1H-indazol-3-amine (68C). MS (m/z) 288.22 [M+H]⁺.

Synthesis of ((S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylamino)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(68E)

The title compound (68E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 55A ofExample 55 utilizingN,1-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(68D). MS (m/z) 576.06 [M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1-methyl-3-(methylamino)-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(68F)

The title compound (68F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 14C ofExample 14 utilizing ((S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylamino)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(68E). MS (m/z) 476.13 [M+H]⁺.

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylamino)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(68G)

The title compound (68G) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1-methyl-3-(methylamino)-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(68F) and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.90-7.86 (m), 7.86-7.80 (m), 7.71(dd), 7.55 (dd), 7.34 (d), 7.22-7.12 (m), 6.84-6.77 (m), 6.77-6.70 (m),6.70-6.67 (m), 6.66-6.62 (m), 6.56 (s), 6.54 (s), 6.47-6.41 (m),6.36-6.29 (m), 5.22 (dd), 5.05 (t), 4.76 (d), 4.71 (s), 3.30-3.22 (m),3.14-3.03 (m), 3.03-2.91 (m), 2.85 (s), 2.46 (ddt), 1.64 (s), 1.44-1.33(m), 1.11-0.97 (m). MS (m/z) 722.18 [M+H]⁺.

Example 69

Synthesis ofN—((S)-1-(3-(3-aminobenzo[d]isoxazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(69)

The title compound (69) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing tert-butyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazol-3-yl)carbamateand2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 7.80 (dd), 7.69 (d), 7.54-7.40 (m), 7.33(dt), 6.57 (ddd), 6.36-6.27 (m), 5.31 (t), 4.82 (s), 3.13-2.96 (m),2.52-2.43 (m), 1.63 (s), 1.45-1.35 (m), 1.15-1.07 (m). MS (m/z) 713.3[M+H]⁺.

Example 70

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(70)

Compound 57-(20 mg, 0.03 mmol) was dissolved in ACN (0.5 ml) and cooledin a salt-ice bath to −10° C. The reaction solution was treated withDABCO (6 mg, 0.05 mmol) then a solution of sulfamoyl chloride (5 mg,0.04 mmol) in ACN (0.2 ml) and let warm to ambient temperature. After 1h, an additional aliquot of DABCO (2 eq) and sulfamoyl chloride (1.5 eq)were added. After another 1.5 hr, the reaction was diluted with KH₂PO₄buffer and partitioned between brine and EtOAc. The organics wereseparated, dried, and removed in vacuo. The residue was purified byreverse phase HPLC to provide the title compound as a mixture ofatropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.69 (d), 7.68 (dd), 7.53(dd), 7.19-7.10 (m), 7.06 (d), 6.87-6.52 (m), 6.49-6.31 (m), 5.35-5.22(m), 5.05-4.94 (m), 4.79-4.65 (m), 3.24 (dd), 3.12 (dd), 3.04-2.91 (m),2.45 (ddt), 1.64 (d), 1.44-1.32 (m), 1.12-0.99 (m). MS (m/z) 820.9[M+H]⁺.

Example 71

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(1,4-dimethyl-3-(sulfamoylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(71)

The title compound (71) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 70 in Example 70utilizing compound 58. ¹H NMR (400 MHz, Methanol-d₄) δ 8.71-8.54 (m),7.73-7.60 (m), 7.57-7.45 (m), 7.08 (d), 7.00-6.89 (m), 6.89-6.77 (m),6.77-6.64 (m), 6.66-6.56 (m), 6.54 (s), 6.44 (d), 6.41-6.33 (m),6.33-6.25 (m), 5.40-5.29 (m), 5.08-4.94 (m), 4.75-4.67 (m), 3.12-2.86(m), 2.86-2.74 (m), 2.54-2.35 (m), 1.44-1.29 (m), 1.12-0.98 (m). MS(m/z) 801.0 [M+H]⁺.

Example 72

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1H-indazol-4-yl)pyridin-2-yl)ethyl)acetamide(72)

The title compound (72) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.74 (d), 8.61 (m), 7.63 (dd), 7.56-7.46(m), 7.39 (dd), 7.32 (dd), 6.99 (d), 6.72 (tt), 6.56-6.45 (m), 6.31 (d),6.27-6.20 (m), 5.44-5.34 (m), 5.10-4.99 (m), 4.93-4.83 (m), 4.76 (s),3.18-3.04 (m), 2.97-2.83 (m), 2.58-2.42 (m), 1.86 (s), 1.67-1.57 (m),1.48-1.33 (m), 1.15 (s), 1.08 (s). MS (m/z) 697.2 [M+H]⁺.

Example 73

Synthesis ofN—((S)-1-(3-(1-aminoisoquinolin-5-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(73)

The title compound (73) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 33F ofExample 33 utilizing5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.89 (d), 8.76 (d), 8.47 (d), 7.90-7.84(m), 7.81-7.73 (m), 7.68-7.50 (m), 7.32 (dd), 7.07 (dd), 6.81-6.69 (m),6.63-6.53 (m), 6.48 (dd), 6.35-6.25 (m), 6.05 (dd), 5.07 (td), 4.86-4.71(m), 3.25-3.09 (m), 3.03-2.92 (m), 2.55-2.45 (m), 1.65 (s), 1.48-1.38(m), 1.16-1.07 (m). MS (m/z) 723.3 [M+H]⁺.

Example 74

Synthesis ofN-(7-bromo-1-methyl-1H-indazol-3-yl)-N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamide(74A)

To N-(7-bromo-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoroacetamide (150mg, 0.47 mmol) in DCE (2 ml) was added iPr₂NEt (0.122 ml, 0.7 mmol)followed by 2,2-difluoroethyl trifluoromethanesulfonate (100 mg, 0.47mmol). The reaction was stirred 15 h at ambient temperature. Thereaction was partitioned between EtOAc and water. The organics wereseparated, dried, and removed in vacuo to provide the title compoundwhich was used directly in the next reaction. MS (m/z) 387.9 [M+H]⁺.

Synthesis of 7-bromo-N-(2,2-difluoroethyl)-1-methyl-1H-indazol-3-amine(74B)

N-(7-bromo-1-methyl-1H-indazol-3-yl)-N-(2,2-difluoroethyl)-2,2,2-trifluoroacetamide(0.18 g, 0.47 mmol) was dissolved in MeOH (2 ml) and treated withaqueous NaOH (1M, 3 ml). After 10 min, the reaction was neutralized andpartitioned between EtOAc and 20% aqueous KH₂PO₄. The organics wereseparated, dried, and removed in vacuo to provide the title compoundwhich was used directly in the next reaction. MS (m/z) 290.1 [M+H]⁺.

Synthesis ofN-(2,2-difluoroethyl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(74C)

The title compound (74C) was prepared according to the method presentedfor the synthesis of 27D in Example 27 utilizing 74B. MS (m/z) 338.1[M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-((2,2-difluoroethyl)amino)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(74D)

The title compound (36C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 27G in Example 27utilizing 14B and 74C. ¹H NMR (400 MHz, Methanol-d₄) δ 7.75 (d), 7.67(dd), 7.52 (dd), 7.18 (d), 7.04 (t), 6.95 (t), 6.85-6.49 (m), 6.39-6.26(m), 6.26-6.20 (m), 6.12-6.04 (m), 5.99-5.91 (m), 5.32-5.22 (m), 5.05(t), 4.74 (s), 3.79-3.56 (m), 3.23-3.11 (m), 3.07 (dd), 3.00-2.89 (m),2.88 (s), 2.54-2.38 (m), 1.64 (s), 1.44-1.27 (m), 1.13-0.94 (m).

MS (m/z) 772.5 [M+H]⁺.

Example 75

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-fluoro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(75)

The title compound (75) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 132C ofExample 132 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.68 (dd), 7.72-7.65 (m), 7.54 (d), 7.51(d), 7.21 (dd), 6.87-6.81 (m), 6.80-6.71 (m), 6.69 (s), 6.66-6.59 (m),6.58 (s), 6.55 (s), 6.45-6.34 (m), 5.35-5.27 (m), 5.03-4.96 (m), 4.88(s), 4.77 (s), 4.72 (d), 3.27-3.08 (m), 3.03-2.92 (m), 2.56-2.37 (m),1.94 (s), 1.64 (d), 1.44-1.26 (m), 1.13-1.06 (m), 1.05-0.98 (m). MS(m/z) 804.1 [M+H]⁺.

Example 76

Synthesis of 2-(3-bromopyridin-2-yl)-N-methylhydrazinecarbothioamide(76B)

3-Bromo-2-hydrazinylpyridine (1500 mg, 7.98 mmol) was dissolved in DCM(50 ml) and treated with dropwise addition of methyl isothiocyanate (700mg, 9.57 mmol) in DCM. The reaction was heated to 45° C. and stirred for2 hr. After cooling to ambient temperature, the solids were filtered toprovide the title compound. MS (m/z) 261.0 [M+H]⁺.

Synthesis of 8-bromo-N-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine(76C)

2-(3-Bromopyridin-2-yl)-N-methylhydrazinecarbothioamide (1.6 g, 6.1mmol) was treated with EDCI HCl (1.76 g, 9 mmol) in toluene and heatedto 105° C. After 1 hr, the hot toluene was decanted. To the residue wasadded H₂O (50 ml). The slurry was mixed thoroughly and heated to 100° C.for 15 min. After cooling to 0° C., the resultant solids were filteredto provide the title compound. MS (m/z) 227.1 [M+H]⁺.

Synthesis of tert-butyl(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(methyl)carbamate (76D)

8-bromo-N-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.55 g, 2.42mmol) was dissolved in DMF (10 ml) and treated with KHMDS (0.58 g, 2.91mmol). Di-tert-butyl dicarbonate (0.79 g, 3.63 mmol) was then added. Thereaction was stirred at ambient temperature for 2 d. The reaction waspartitioned between EtOAc and water. The organics were separated, dried,and removed in vacuo and the residue was purified by columnchromatography on silica to provide the title compound. MS (m/z) 326.9[M+H]⁺.

Synthesis of(3-((tert-butoxycarbonyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)boronicacid (76E)

tert-Butyl (8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(methyl)carbamate(0.46 g, 1.41 mmol) was combined with bis(pinacolato)diboron (0.54 g),KOAc (0.41 g, 0 mol), and PdCl₂(PCy₃)₂ (0.05 g) in dioxane and DMF.Argon was bubbled into the reaction mixture for 10 min and then heatedto 140 deg C. for 2 h. The reaction was partitioned between EtOAc andwater. The organics were separated, dried, and removed in vacuo toprovide the title compound as a crude product contaminated withbyproducts. The material was used directly in the following reaction. MS(m/z) 293.0 [M+H]⁺.

Synthesis of2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-(methylamino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)acetamide(76F)

The title compound (76F) was prepared according to the method presentedfor the synthesis of 27G in Example 27 utilizing 14B and 76E. ¹H NMR(400 MHz, Methanol-d₄) δ 8.88 (d), 8.22 (d), 7.75 (d), 7.56 (d), 7.37(s), 7.18 (t), 6.67 (t), 6.70-6.59 (m), 6.55-6.44 (m), 5.31-5.17 (m),4.69 (d), 3.23-3.08 (m), 2.55-2.39 (m), 1.63 (s), 1.46-1.25 (m),1.08-1.00 (m). MS (m/z) 709.2 [M+H]⁺.

Example 77

Synthesis of 3-amino-7-bromo-1-methyl-1H-indazole-4-carbonitrile (77A)

To 58B (3 g, 8.5 mmol) in dioxane (32 mL) and DMF (32 ml) was added zinc(6.7 g, 102.3 mmol) and Pd(PPh₃)₂Cl₂ (600 mg, 0.9 mmol). The reactionmixture was stirred at 160° C. and ZnCN₂ (500 mg, 4.3 mmol) was added tothe reaction. After an hour another aliquot of ZnCN₂ (500 mg, 4.3 mmol)was added. The reaction was cooled, diluted with EtOAc and brine. Themixture was extracted 2× with EtOAc, the organic layer was dried oversodium sulfate, was concentrated and purified by flash columnchromatography to provide the title compound. MS (m/z) 251.1 [M+H]⁺.

Synthesis of3-amino-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carbonitrile(77B)

The title compound (77B) was prepared according to the method presentedfor the synthesis of compound 19C of Example 19 utilizing 77A. MS (m/z)299.3 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-4-cyano-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(77C)

The title compound (77C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing 77B. MS (m/z) 587.0 [M+H]⁺.

Synthesis of(S)-3-amino-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazole-4-carbonitrile(77D)

The title compound (77D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 77C. MS (m/z) 487.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-4-cyano-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(77E)

The title compound (77E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 77D and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.54 (t), 7.52-7.45 (m), 7.33 (d), 7.19(t), 6.85 (t), 6.71-6.62 (m), 6.49 (d), 6.24-6.17 (m), 6.15 (d), 5.47(d), 4.99-4.88 (m), 4.78-4.68 (m), 3.12 (s), 3.03-2.94 (m), 2.92 (s),2.56-2.39 (m), 1.72 (s), 1.42 (q), 1.21-1.10 (m) MS (m/z) 733.3 [M+H]⁺.

Example 78

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(78)

The title compound (78) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19G ofExample 19 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.60-7.46 (m), 7.32-7.24 (m), 7.24-7.15(m), 6.92 (d), 6.71-6.62 (m), 6.48 (s), 6.27-6.17 (m), 6.08 (d), 5.55(d), 4.98 (q), 4.79 (d), 4.73 (d), 3.56 (d), 3.40 (d), 3.27 (s),3.07-2.91 (m), 2.66-2.40 (m), 1.71 (s), 1.44 (q), 1.28-1.15 (m). MS(m/z) 838.9 [M+H]⁺.

Example 79

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-methyl-1H-indazol-4-yl)pyridin-2-yl)ethyl)acetamide(79)

The title compound (79) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 20F ofExample 20 utilizing (3-carbamoyl-4-chlorophenyl)boronic acid and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd3od) δ 8.75 (d), 8.61 (d), 7.63 (dd), 7.56-7.46(m), 7.39 (dd), 7.32 (dd), 6.99 (d), 6.72 (tt), 6.56-6.45 (m), 6.31 (d),6.27-6.20 (m), 5.39 (dt), 5.10-4.99 (m), 4.76 (s), 3.18-3.04 (m),2.97-2.83 (m), 2.58-2.42 (m), 1.86 (s), 1.64 (d), 1.60 (s), 1.48-1.33(m), 1.18-1.11 (m), 1.11-1.03 (m). MS (m/z) 711.7 [M+H]⁺.

Example 80

Synthesis of2-chloro-5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)benzamide(80)

The title compound (80) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing(3-carbamoyl-4-chlorophenyl)boronic acid and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.86 (d), 7.54 (d), 7.46 (dd), 7.17 (d),7.07-6.99 (m), 6.70 (tt), 6.44-6.34 (m), 5.35 (dd), 4.84 (d), 3.19-3.00(m), 2.57-2.42 (m), 1.62 (s), 1.46-1.36 (m), 1.15-1.06 (m). MS (m/z)736.0 [M+H]⁺.

Example 81

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(81)

The title compound (81) was prepared as a mixture of atropisomersaccording to the method presented in Example 68 utilizing7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (19B) in place of7-bromo-1-methyl-1H-indazol-3-amine (33A). ¹H NMR (400 MHz, Methanol-d₄)δ 7.90-7.86 (m), 7.86-7.80 (m), 7.71 (dd), 7.55 (dd), 7.34 (d),7.22-7.12 (m), 6.84-6.77 (m), 6.77-6.70 (m), 6.70-6.67 (m), 6.66-6.62(m), 6.56 (s), 6.54 (s), 6.47-6.41 (m), 6.36-6.29 (m), 5.22 (dd), 5.05(t), 4.76 (d), 4.71 (s), 3.30-3.22 (m), 3.14-3.03 (m), 3.03-2.91 (m),2.85 (s), 2.46 (ddt), 1.64 (s), 1.44-1.33 (m), 1.11-0.97 (m). MS (m/z)756.14 [M+H]⁺.

Example 82

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(82)

The title compound (82) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19G ofExample 19 utilizing2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.60-7.47 (m), 7.31-7.16 (m), 7.02-6.80(m), 6.72-6.59 (m), 6.51-6.43 (m), 6.27-6.12 (m), 5.66-5.52 (m),5.08-4.97 (m), 4.94 (d), 3.40 (s), 3.38 (s), 3.28 (t), 3.07 (s),3.01-2.89 (m), 2.63-2.42 (m), 2.03 (s), 1.71 (s). MS (m/z) 858.8 [M+H]⁺.

Example 83

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamide(83)

The title compound (83) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19G ofExample 19 utilizing2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.55-7.43 (m), 7.38 (d), 7.29 (d), 7.18(d), 6.96 (dd), 6.86 (d), 6.72 (d), 6.67-6.59 (m), 6.57 (d), 6.29 (d),6.18 (td), 4.94 (dq), 4.84-4.79 (m), 4.76 (s), 3.39 (d), 3.30 (s), 3.24(s), 3.07 (d), 3.01-2.89 (m), 2.89-2.74 (m), 2.63-2.47 (m), 2.29-2.08(m), 1.82-1.62 (m), 1.71 (d), 1.05 (td), 0.96 (td), 0.74 (q), 0.65 (q).MS (m/z) 798.9 [M+H]⁺.

Example 84

Synthesis ofN—((S)-1-(3-(4-chloro-3-(2-methoxyacetamido)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(84)

To the reaction vial containing 57-(13 mg, 0.017 mmol) in THF (0.25 mL)was added 2-methoxyacetyl chloride (2 mg, 0.019 mmol), and triethylamine(0.004 mL, 0.026 mmol). The reaction mixture was stirred at roomtemperature until the majority of 57 was consumed. The reaction mixturewas concentrated in vacuo and dissolved in methanol and treated withseveral drops of 2 M NaOH for 30 min. The reaction mixture was thenacidified with TFA and purified by reverse phase HPLC to provide thetitle compound 84 as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od)δ 8.72-8.67 (m), 7.70 (dd), 7.54 (dd), 7.22-7.13 (m), 7.08 (d),6.87-6.59 (m), 6.50-6.36 (m), 5.32-5.25 (m), 5.02-4.94 (m), 4.72 (dd),4.14 (d), 3.56 (s), 3.34 (s), 3.15 (dd), 3.05-2.93 (m), 2.51-2.38 (m),1.64 (d), 1.45-1.31 (m), 1.11-1.05 (m), 1.06-0.97 (m). MS (m/z) 815.2[M+H]⁺.

Example 85

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-3-methoxypropanamide(85)

The title compound (85) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing 3-methoxypropanoyl chloride. ¹H NMR (400 MHz,cd₃od) δ 8.75-8.65 (m), 7.69 (dd), 7.53 (dd), 7.21-7.12 (m), 7.07 (d),6.87-6.52 (m), 6.47-6.35 (m), 5.35-5.25 (m), 4.98 (t), 4.79-4.63 (m),3.79-3.73 (m), 3.39 (s), 3.14 (dd), 3.05-2.93 (m), 2.76-2.68 (m),2.51-2.39 (m), 1.64 (d), 1.45-1.32 (m), 1.11-1.05 (m), 1.06-0.97 (m). MS(m/z) 829.2 [M+H]⁺.

Example 86

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)cyclopropanecarboxamide(86)

The title compound (86) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing cyclopropanecarbonyl chloride. ¹H NMR (400 MHz,cd₃od) δ 8.75-8.52 (m), 7.69 (dd), 7.53 (dd), 7.16 (d), 7.06 (d),6.87-6.52 (m), 6.46-6.35 (m), 5.35-5.21 (m), 4.98 (t), 4.79-4.63 (m),3.14 (dd), 3.00 (d), 2.53-2.39 (m), 1.90 (s), 1.64 (d), 1.45-1.32 (m),1.06-0.96 (m), 0.90 (s). MS (m/z) 811.2 [M+H]⁺.

Example 87

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)isoxazole-5-carboxamide(87)

The title compound (87) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing isoxazole-5-carbonyl chloride. ¹H NMR (400 MHz,cd₃od) δ 8.71 (t), 8.60 (s), 7.72 (dd), 7.55 (dd), 7.24-7.07 (m),6.87-6.61 (m), 6.60-6.37 (m), 5.35-5.25 (m), 5.00 (t), 4.79-4.64 (m),3.37 (s), 3.21-3.12 (m), 3.08-2.95 (m), 2.52-2.39 (m), 1.92 (d), 1.64(d), 1.42-132 (m), 1.08 (s), 1.02 (s). MS (m/z) 838.1 [M+H]⁺.

Example 88

Synthesis ofN—((S)-1-(3-(4-chloro-3-(2-hydroxyacetamido)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(88)

The title compound (88) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing 2-chloro-2-oxoethyl acetate. ¹H NMR (400 MHz,cd₃od) δ 7.74-7.66 (m), 7.54 (dd), 7.23-7.13 (m), 7.08 (d), 6.87-6.58(m), 6.50-6.35 (m), 5.25-5.31 (m), 4.99 (t), 4.76 (d), 4.68 (s), 4.21(d), 3.34 (s), 3.30-3.11 (m), 3.04-2.94 (m), 2.51-2.38 (m), 1.64 (d),1.45-1.33 (m), 1.11-1.05 (m), 1.06-0.97 (m). MS (m/z) 802.1 [M+H]⁺.

Example 89

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-2-hydroxy-2-methylpropanamide(89)

The title compound (89) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing 1-chloro-2-methyl-1-oxopropan-2-yl acetate. ¹H NMR(400 MHz, cd₃od) δ 8.75-8.65 (m), 7.70 (t), 7.54 (dd), 7.22-7.12 (m),7.07 (d), 6.87-6.66 (m), 6.49-6.36 (m), 5.30-5.22 (m), 4.99 (t), 4.75(d), 4.67 (s), 3.35 (s), 3.28-3.12 (m), 3.04-2.93 (m), 2.49-2.38 (m),1.64 (d), 1.51 (dd), 1.43-1.33 (m), 1.08 (s), 1.05-0.98 (m). MS (m/z)829.2 [M+H]⁺.

Example 90

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(90A)

The title compound (90A) was prepared according to the method presentedfor the synthesis of compound (14B) of Example 14 utilizingtert-butyldimethyl((2-methylbut-3-yn-2-yl)oxy)silane. MS (m/z) 609.10[M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(90B)

The title compound (90B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (19E) ofExample 19 utilizing (S)-tert-butyl(1-(3-bromo-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(90A) and4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(19C). MS (m/z) 710.01 [M+H]⁺.

Synthesis of (S)-methyl(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)carbamate(90C)

To a solution of (S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(90B) (20 mg, 0.03 mmol) and DIPEA (0.08 μl, 0.06 mmol) indichloromethane (0.5 ml) was added methyl chloroformate (3.27 μl, 0.04mmol). After stirring overnight, trifluoroacetic acid (0.5 ml) was addedand the reaction was stirred at room temperature for 1 hour. Thereaction was concentrated, extracted with ethyl acetate, and basifiedwith 2 M aqueous K₂CO₃. The organic layer was washed with 0.5 M NaCl andthe organic layer was dried with Na₂SO₄, filtered, and concentrated. Thecrude product as a mixture of atropisomers was taken to the next stepwithout further purification. MS (m/z) 554.13 [M+H]⁺.

Synthesis of methyl(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)carbamate(90D)

The title compound (90D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (33F) ofExample 33 utilizing (S)-methyl(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)carbamate(90C) and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.72 (d), 8.66 (d), 7.74-7.63 (m),7.59-7.48 (m), 7.20-7.14 (m), 7.07 (d), 6.87-6.53 (m), 6.46-6.33 (m),5.35-5.26 (m), 5.05-4.95 (m), 4.80-4.64 (m), 3.75 (d), 3.33 (s),3.28-3.07 (m), 2.99 (q), 2.53-2.39 (m), 1.64 (s), 1.50-1.28 (m), 1.09(d), 1.06-0.99 (m). MS (m/z) 800.15 [M+H]⁺.

Example 91

Synthesis of (S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-1-methyl-3-(2,2,2-trifluoroacetamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(91A)

To a solution of (S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(90B) (93 mg, 0.13 mmol) in dichloromethane (0.5 ml) was added DIPEA(34.14 μl, 0.2 mmol), followed by trifluoroacetic anhydride (25.5 μl,0.18 mmol). After stirring at room temperature for 1 h, the product wasextracted with dichloromethane and water. The organic layer was driedwith Na₂SO₄, filtered, concentrated in vacuo, and purified by silica gelchromatography to provide the title compound. MS (m/z) 806.04 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-3-(N-ethyl-2,2,2-trifluoroacetamido)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(91B)

To a solution of (S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-1-methyl-3-(2,2,2-trifluoroacetamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(91A) (20 mg, 0.02 mmol) in DMF (0.5 ml) was added cesium carbonate(20.2 mg, 0.06 mmol), followed by diethylsulfate (4.6 mg, 0.03 mmol).After stirring at room temperature overnight, the reaction mixture wasextracted with ethyl acetate and water. The organic layer was dried withNa₂SO₄, filtered, and concentrated in vacuo. The crude product was takento the next step without further purification.

Synthesis of (S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-3-(ethylamino)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(91C)

To a solution of (S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-3-(N-ethyl-2,2,2-trifluoroacetamido)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(21 mg) (91B) in methanol (0.5 mL) was added 2M aqueous K₂CO₃ (0.25 mL).After stirring at room temperature for 2 h, the reaction mixture wasconcentrated in vacuo. The mixture was extracted with ethyl acetate andwater. The organic layer was dried with Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was taken to the next stepwithout further purification.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(4-chloro-3-(ethylamino)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(91D)

The title compound (91D) was prepared according to the method presentedfor the synthesis of compound (90C) of Example 90 utilizing(S)-tert-butyl(1-(6-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(4-chloro-3-(ethylamino)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(91C). MS (m/z) 524.55 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-(ethylamino)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(91E)

The title compound (91E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (90D) ofExample 90 utilizing(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(4-chloro-3-(ethylamino)-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(91D). ¹H NMR (400 MHz, Methanol-d₄) δ 7.73-7.60 (m), 7.58-7.48 (m),7.12 (d), 7.04 (d), 6.93 (d), 6.85-6.79 (m), 6.78-6.71 (m), 6.71-6.66(m), 6.67-6.58 (m), 6.58-6.53 (m), 6.49-6.32 (m), 6.32-6.28 (m),5.26-5.20 (m), 5.04 (t), 4.80-4.67 (m), 4.10 (q), 3.42-3.28 (m),3.27-3.17 (m), 3.17-3.05 (m), 3.05-2.91 (m), 2.82 (s), 2.53-2.40 (m),2.01 (s), 1.64 (s), 1.41-1.21 (m), 0.96-0.82 (m). MS (m/z) 770.15[M+H]⁺.

Example 92

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-ureido-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(92)

To a solution ofN—((S)-1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(57) (30 mg, 0.04 mmol) in acetic acid (0.4 ml) was added a solution ofpotassium cyanate (3.9 mg, 0.049 mmol) in water (0.05 ml). Afterstirring at 50° C. for 2 h, the reaction was concentrated and purifiedby reverse phase HPLC to provide the title product as a mixture ofatropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.72 (dd), 7.69 (dd), 7.54(dd), 7.22-7.10 (m), 7.04 (d), 6.88-6.52 (m), 6.47-6.32 (m), 5.31-5.22(m), 5.03-4.92 (m), 4.76 (s), 4.72 (d), 3.28 (s), 3.18-3.10 (m),3.04-2.94 (m), 2.94 (s), 2.53-2.40 (m), 1.64 (s), 1.46-1.25 (m),1.12-1.05 (m), 1.05-0.99 (m). MS (m/z) 785.15 [M+H]⁺.

Example 93

Synthesis ofN—((S)-1-(3-(4-chloro-3-((cyanomethyl)amino)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(93)

The title compound (93) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (91D) ofExample 91 utilizing bromoacetonitrile in place of diethyl sulfateduring the synthesis of compound (91B). ¹H NMR (400 MHz, Methanol-d₄) δ8.69 (d), 8.63-8.55 (m), 7.67 (dd), 7.56-7.48 (m), 7.11 (d), 6.99 (d),6.86 (dd), 6.78-6.72 (m), 6.70 (d), 6.67-6.60 (m), 6.57 (d), 6.45-6.31(m), 5.35-5.28 (m), 5.08-5.00 (m), 4.77 (s), 4.73 (s), 4.35-4.23 (m),3.20 (s), 3.12 (dd), 3.05-2.92 (m), 2.89 (s), 2.54-2.39 (m), 1.64 (s),1.44-1.30 (m), 1.12-1.07 (m), 1.07-1.01 (m). MS (m/z) 828.18 [M+H]⁺.

Example 94

Synthesis ofN—((S)-1-(3-(3-acetamido-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(94)

The title compound (94) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing acetyl chloride. ¹H NMR (Chloroform-d) δ: 7.63-7.57(m), 7.54-7.48 (m), 7.25-7.22 (m), 6.97 (d), 6.70 (t), 6.70-6.63 (m),6.48 (t), 6.24 (d), 6.19 (d), 6.15 (d), 5.63-5.55 (m), 4.99 (q), 4.76(d), 4.70 (d), 3.29 (s), 3.09-2.94 (m), 2.55-2.40 (m), 2.30 (d), 1.72(d), 1.41 (q), 1.21-1.12 (m). MS (m/z) 784.9 [M+H]⁺.

Example 95

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)propionamide(95)

The title compound (95) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing propionyl chloride. ¹H NMR (Chloroform-d) δ:7.62-7.43 (m), 7.35-7.17 (m), 6.95 (d), 6.71 (t), 6.69-6.62 (m),6.53-6.44 (m), 6.30-6.16 (m), 6.12 (d), 5.61-5.50 (m), 4.96 (q), 4.75(d), 4.70 (d), 3.28 (s), 3.07 (s), 2.95 (d), 2.56 (qd), 2.61-2.36 (m),1.71 (s), 1.41 (q), 1.36-1.21 (m), 1.20-1.08 (m). MS (m/z) 798.9 [M+H]⁺.

Example 96

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)isobutyramide(96)

The title compound (96) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing isobutyryl chloride. ¹H NMR (Chloroform-d) δ:7.59-7.52 (m), 7.48 (dd), 7.31-7.23 (m), 7.22 (s), 6.94 (d), 6.70 (t),6.69-6.61 (m), 6.48 (d), 6.22 (d), 6.18 (d), 6.11 (d), 5.56 (d), 4.96(q), 4.75 (d), 4.69 (d), 3.28 (s), 3.15 (s), 3.09 (s), 2.96 (d), 2.72(s), 2.55-2.40 (m), 1.71 (s), 1.41 (q), 1.33 (s), 1.21-1.13 (m). MS(m/z) 813.1 [M+H]⁺.

Example 97

Synthesis ofN-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-2,2-difluoroacetamide(97)

The title compound (97) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing 2,2-difluoroacetic anhydride. ¹H NMR (Chloroform-d)δ: 8.80 (d), 7.63-7.55 (m), 7.54-7.46 (m), 7.43-7.30 (m), 7.30-7.23 (m),6.99 (d), 6.71 (t), 6.70-6.63 (m), 6.53-6.46 (m), 6.25 (d), 6.19 (d),6.17-6.11 (m), 6.04-5.95 (m), 5.65-5.53 (m), 4.98 (q), 4.79-4.73 (m),4.69 (d), 3.33 (s), 3.12 (s), 3.07-2.94 (m), 2.60-2.34 (m), 1.71 (s),1.41 (q), 1.26 (s), 1.23-1.12 (m) MS (m/z) 820.9 [M+H]⁺.

Example 98

SynthesisN-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(98)

The title compound (98) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing 2,2,2-trifluoroacetic anhydride. ¹H NMR(Chloroform-d) δ: 8.77-8.72 (m), 8.69-8.63 (m), 7.56-7.43 (m), 7.31-7.19(m), 7.18-7.06 (m), 7.01-6.95 (m), 6.71 (t), 6.70-6.61 (m), 6.52-6.45(m), 6.24-6.16 (m), 6.11 (d), 5.60-5.52 (m), 4.93 (q), 4.75 (d), 4.69(d), 3.32 (s), 3.10 (s), 3.01-2.91 (m), 2.57-2.38 (m), 2.23-2.02 (m),1.72 (s), 1.47-1.37 (m), 1.25 (s), 1.22-1.12 (m). MS (m/z) 838.8 [M+H]⁺.

Example 99

Synthesis of2-bromo-N-(4-chloro-7-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)acetamide(99A)

To the reaction vial containing 57-(32 mg, 0.043 mmol) in THF (0.25 mL)was added 2-bromoacetyl chloride (7 mg, 0.047 mmol), and triethylamine(0.009 mL, 0.06 mmol). The reaction mixture was stirred at roomtemperature until the majority of 57 was consumed. The reaction mixturewas concentrated in vacuo and telescoped to the next reaction. MS (m/z)862.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-(2-(dimethylamino)acetamido)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(99B)

The crude 99A material was dissolved in DMF (0.1 mL) and treated withexcess dimethylamine at room temperature for 30 min. The reactionmixture was then acidified with TFA and purified by reverse phase HPLCto provide the title compound 99B as a mixture of atropisomers. ¹H NMR(400 MHz, cd₃od) δ 8.90-8.69 (m, 1H), 7.73-7.65 (m, 1H), 7.59-7.49 (m,1H), 7.23-7.06 (m, 1H), 6.89-6.59 (m, 2H), 6.53-6.29 (m, 3H), 5.03-4.93(m, 1H), 4.80-4.68 (m, 2H), 4.28 (s, 2H), 3.38-2.96 (m, 9H), 2.91-2.73(m, 2H), 2.61-2.33 (m, 2H), 1.64 (s, 6H), 1.43-1.28 (m, 1H), 1.15-0.98(m, 1H). MS (m/z) 829.2 [M+H]⁺.

Example 100

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(2-(pyrrolidin-1-yl)acetamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(100)

The title compound (100) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 99B ofExample 99 utilizing pyrrolidine. ¹H NMR (400 MHz, cd₃od) δ 8.87-8.69(m), 7.73-7.68 (m), 7.59-7.49 (m), 7.20 (s), 7.10 (s), 6.90-6.69 (m),6.45-6.32 (m), 5.30-5.25 (m), 5.03-4.98 (m), 4.79-4.63 (m), 4.37 (s),3.82-3.64 (m), 3.35 (s), 3.24-3.19 (m), 3.01 (s), 2.51-2.43 (m, 2H),2.30-2.13 (m), 1.64 (d), 1.42-1.25 (m), 1.10 (s), 1.00 (s). MS (m/z)854.4 [M+H]⁺.

Example 101

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(2-(methylamino)acetamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(101)

The title compound (101) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 99B ofExample 99 utilizing methylamine. ¹H NMR (400 MHz, cd₃od) δ 8.85-8.65(m), 7.79-7.62 (m), 7.60-7.50 (m), 7.21-7.15 (m), 7.13-7.09 (m),6.91-6.50 (m), 6.45-6.23 (m), 5.32-5.21 (m), 5.00-4.98 (m), 4.82-4.68(m), 4.20-4.15 (s), 4.14-4.08 (s), 3.35 (s), 3.13-3.08 (m), 3.03-2.98(m), 2.81 (s), 2.48-2.43 (m), 1.64 (d), 1.50-1.29 (m), 1.12-1.05 (m),1.03-0.98 (m). MS (m/z) 814.2 [M+H]⁺.

Example 102

Synthesis ofN—((S)-1-(3-(4-chloro-3-(2-(cyclopropylamino)acetamido)-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(102)

The title compound (102) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 99B ofExample 99 utilizing cyclopropylamine. ¹H NMR (400 MHz, cd₃od) δ8.74-8.69 (m), 7.74-7.65 (m), 7.59-7.49 (m), 7.19 (s), 7.12 (s)6.91-6.53 (m), 6.38 (m), 5.35-5.20 (m), 5.01-4.94 (m), 4.79-4.64 (m),4.21 (s), 3.35 (s), 3.03-2.98 (m), 2.91-2.86 (m), 2.53-2.38 (m), 1.64(s), 1.45-1.36 (m), 1.11-0.70 (m). MS (m/z) 840.2 [M+H]⁺.

Example 103

Synthesis of(S)—N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)-2-hydroxypropanamide(103)

The title compound (103) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 84 ofExample 84 utilizing (S)-1-chloro-1-oxopropan-2-yl acetate. ¹H NMR (400MHz, cd₃od) δ 8.72-8.64 (m), 7.70 (dd), 7.54 (dd), 7.22-7.12 (m), 7.07(d), 6.87-6.66 (m), 6.50-6.36 (m), 5.30-5.25 9 (m), 4.99 (t), 4.75 (d),4.68 (s), 4.38-4.28 (m), 3.33 (s), 3.26-3.12 (m)), 3.04-2.93 (m),2.52-2.38 (m), 1.64 (d), 1.50 (dd), 1.43-1.31 (m), 1.10-1.05 (m),1.04-0.98 (m). MS (m/z) 815.2 [M+H]⁺.

Example 104

Synthesis ofN—((S)-1-(6-(3-amino-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(104)

The title compound (104) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (61) ofExample 61 utilizing 2-methylbut-3-yn-2-amine ¹H NMR (400 MHz,Methanol-d4) δ 8.71 (d), 7.89-7.81 (m), 7.78 (t), 7.63 (dd), 7.27 (dd),7.20 (dd), 7.10 (dd), 6.79-6.71 (m), 6.68-6.58 (m), 6.52 (dd), 6.40-6.27(m), 5.33-5.24 (m), 5.02 (q), 4.80-4.68 (m), 3.32 (s), 3.28-3.20 (m),3.18 (s), 3.16-3.10 (m), 3.04-2.91 (m), 2.58-2.40 (m), 1.83 (s),1.47-1.36 (m), 1.15-1.10 (m), 1.08-1.02 (m). MS (m/z) 803.13 [M+H]⁺.

Example 105

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6′-hydrazinyl-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-[3,3′-bipyridin]-2-yl)ethyl)carbamate(105A)

In a microwave tube were charged with compound 14B (50 mg, 0.1 mmol),2-hydrazinyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (36mg, 0.15 mmol), potassium carbonate (42 mg, 0.3 mmol) anddichlorobis(tricyclohexylphosphine)palladium(II) (4 mg, 0.005 mmol). Tothe mixture was added was added 1,4-dioxane (2 mL), water (0.5 mL) andMeOH (0.3 mL). The mixture was heated to 150° C. for 10 minutes in amicrowave synthesizer. After cooling to room temperature, the reactionwas partitioned between EtOAc and water. The organic layer was separatedand washed with brine, then dried over MgSO₄, filtered and concentrated.The residue was purified by silica gel chromatography to afford thetitle compound 105A. MS (m/z): 524.10 [M+H]⁺;

Synthesis of Boc-(S)-ethyl(6-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate(105B)

To a reaction mixture of compound 105A (28 mg, 0.053 mmol) in 0.5 mL2-methyltetrahydrofuran was added ethoxycarbonyl isothiocyanate (7 mg,0.053 mmol) and the reaction was allowed to stir at room temperature for1 min. The solvent was removed in vacuo. The residue was dissolved in0.5 mL of methylene chloride and to it was added2-chloro-1-methylpyridinium iodide (12 mg, 0.046 mmol) followed bytriethylamine (0.08 mL, 0.057 mmol). The reaction mixture was stirred atroom temperature for 1 min. The solvent was removed in vacuo and theresidue was purified by silica gel chromatography to afford the titlecompound 105B. MS (m/z): 621.07 [M+H]⁺.

Synthesis of (S)-ethyl(6-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate(105C)

Compound 105B (14 mg, 0.023 mmol) was dissolved in 1 mL of methylenechloride and to it was added 0.15 mL of TFA. The reaction mixture wasstirred at room temperature for 40 minutes. The solvent was removed toafford the title compound 105C as a TFA salt. MS (m/z): 521.09 [M+H]⁺.

Synthesis of ethyl(6-(2-((S)-1-(2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate(105D)

The title compound (105D) was prepared according to the method presentedfor the synthesis of compound 37E of Example 37 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 105C. MS (m/z) 767.18 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(105E)

Compound 105D (15.3 mg, 0.05 mmol) was dissolved in 2 mL of 1,4-dioxaneand to it was added 0.5 mL of 1M sodium bicarbonate aqueous solution.The reaction mixture was heated in microwave for 1 hour at 140° C. Thesolvent was removed and the residue was purified by RP-HPLC to affordthe title compound 105E. ¹H NMR (400 MHz, Methanol-d₄): δ 8.08 (s),7.81-7.60 (m), 7.57-7.38 (m), 6.77-6.70 (m), 6.61 (t), 6.52-6.35 (m),5.36 (t), 4.81 (d), 3.15 (d), 2.59-2.27 (m), 1.63 (s), 1.48-1.20 (m),1.10-0.78 (m). MS (m/z): 695.30 [M+H]⁺.

Example 106

Synthesis of 3-bromo-6-chloro-2-hydrazinylpyridine (106A)

To a mixture of 3-bromo-6-chloro-2-fluoropyridine (6 g, 28.5 mmol) in200 mL ethanol was added 14 mL of hydrazine monohydrate. The reactionmixture was stir at room temperature for overnight and then removed mostof the solvent. The precipitate was collected by vacuum filtration toafford the title compound 106A. MS (m/z): 223.97 [M+H]⁺.

Synthesis of ethyl(8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate (106B)

The title compound (106B) was prepared according to the method presentedfor the synthesis of compound 105B of Example 105 utilizing compound106A. MS (m/z) 321.01 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(106C)

In a microwave tube were charged with compound 117B (48 mg, 0.1 mmol),compound 106B (40 mg, 0.13 mmol), sodium carbonate (33 mg, 0.03 mmol)and PdCl₂[PPh₃]₂ (8 mg, 0.01 mmol). To the mixture was added 2.5 mL of1,4-dioxane and 0.5 mL of water. The mixture was heated to 170° C. for20 minutes in a microwave synthesizer. After cooling to roomtemperature, the reaction was partitioned between EtOAc and water. Theorganic layer was separated and washed with brine, then dried overMgSO₄, filtered and concentrated. The residue was purified by reversephase HPLC to afford the title compound 106C. MS (m/z): 583.01 [M+H]⁺

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(106D)

The title compound (106D) was prepared according to the method presentedfor the synthesis of compound 105C of Example 105 utilizing compound106C. MS (m/z) 483.28 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(106E)

The title compound (106E) was prepared according to the method presentedfor the synthesis of compound 37E of Example 37 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 106D. ¹H NMR (400 MHz, Methanol-d₄): δ 8.79 (d), 7.71(d), 7.52 (d), 7.04 (d), 6.69-6.63 (m), 6.68 (t), 6.59-6.36 (m),5.41-5.12 (m), 4.75-4.48 (m), 3.25-2.97 (m), 2.55-2.35 (m), 1.62 (s),1.38 (q), 1.12-0.96 (m). MS (m/z): 729.24 [M+H]⁺.

Example 107

Synthesis of 7-bromo-1-methyl-1H-indazol-3-ol (107A)

To the reaction vial containing methyl 3-bromo-2-fluorobenzoate (1 g,4.5 mmol) in ethanol (5 mL) was added methylhydrazine (0.29 mL, 6 mmol).The reaction mixture was sealed and heated to 125° C. overnight. Uponcooling, the reaction mixture was treated with water and the resultingsolid was collected by filtration to give the title product 107A. MS(m/z) 229.1 [M+2H]⁺.

Synthesis of2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-oxo-2,3-dihydro-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(107B)

The title compound (107B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 117F ofExample 117 utilizing 107A and 117B. ¹H NMR (400 MHz, cd₃od) δ 8.61 (d),7.79-7.63 (m), 7.52 (dd), 7.28-7.21 (m), 7.12 (t), 7.02 (t), 6.76-6.67(m), 6.66-6.54 (m), 6.40 (d), 6.34-6.27 (m), 5.26 (t), 5.17-5.07 (m),4.83-4.74 (m), 3.24 (dd), 3.12-2.88 (m), 2.75 (s), 2.55-2.42 (m), 1.64(s), 1.45-1.35 (m), 1.14-1.06 (m). MS (m/z) 727.1 [M+H]⁺.

Example 108

Synthesis of 7-bromo-4-chloro-1H-indazol-3-amine (108A)

In a microwave vial a solution of 3-bromo-2-fluorobenzonitrile (1 g,4.26 mmol) ethanol (5 mL) was treated with hydrazine (0.85 mL, 17 mmol),sealed, and heated to 120° C. in a microwave reactor for 35 minutes. Thereaction was concentrated in vacuo and the crude product dissolved withEtOAc (30 mL) and washed with water (30 mL), then 2M NaCl (aq, 30 mL).The organics were dried with Na₂SO₄, filtered, and concentrated. Productwas purified by silica chromatography to give the title compound. MS(m/z) 247.1 [M+H]⁺.

Synthesis of N-(7-bromo-4-chloro-1H-indazol-3-yl)methanesulfonamide(108B)

To a stirred solution of 108A (161 mg, 0.65 mmol),4-dimethylaminopyridine (4 mg, 0.03 mmol), and N,N-diisopropylethylamine(0.28 mL, 1.6 mmol) in DCM (5 ml) at, 0° C. was added drop wisemethanesulfonyl chloride (156 mg, 1.3 mmol). The ice bath was removedimmediately after the addition and the reaction was warmed to roomtemperature and stirred for 2 h. The reaction was washed with water,dried with Na₂SO₄, filtered, and concentrated. The crude productdissolved with EtOH (10 mL) and treated with 8N NaOH (3.3 ml). Thereaction mixture was heated at 60° C. for 0.5 h. The ethanol was removedunder vacuum, pH to ˜2 with 1.0HCl then, extracted with EtOAc. Theorganics were dried with Na₂SO₄, filtered, and concentrated. The productwas purified by silica chromatography to give the title compound. MS(m/z) 325.9 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(108C)

The title compound (108C) was prepared according to the method presentedfor the synthesis of compound 117F of Example 117 utilizing 108B and117B. MS (m/z) 807.1 [M+H]⁺. HPLC retention time 6.96 min (2-98%acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on aPhenomonex Kinetex C18 column).

Example 109

Synthesis ofN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(109)

The title compound (109) was prepared according to the method presentedfor the synthesis of compound 117F of Example 117 utilizing 108B, 117Band2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. MS (m/z) 824.2 [M+H]⁺. HPLC retention time 7.16 min (2-98%acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on aPhenomonex Kinetex C18 column).

Example 110

Synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-amine(110A)

To a solution of compound 106B (2.1 g, 6.6 mmol) in a mixture of dioxane(90 mL), water (15 mL) and DMF (9 mL) was added KOH (0.37 g, 6.6 mmol).The mixture was heated at 110° C. overnight. After removing volatiles invacuo, the residue was purified by silica gel column to yield the titlecompound 110A. MS (m/z) 248.95 [M+H]⁺.

Synthesis ofN-(8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamide(110B)

To a solution of compound 110A (80 mg, 0.3 mmol) in DCM (5 mL) was addedDIEA (0.42 g, 3 mmol) and methanesulfonyl chloride (0.19 g, 2 mmol).After stirred at room temperature for 5 min, the volatiles was removedin vacuo. The residue was dissolved in a mixture of THF (2 mL), MeOH (2mL) and 2 N NaOH (2 mL) and stirred for 15 min. After removingvolatiles, the residue was purified by reverse phase HPLC to yield thetitle compound. MS (m/z) 326.82 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(5-chloro-3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(110C)

The title compound (110C) was prepared according to the method presentedfor the synthesis of compound 117D of Example 117 utilizing compound110B and 117B. MS (m/z) 661.02 [M+H]⁺.

Synthesis of(S)—N-(8-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamideTFA salt (110D)

The title compound (110D) was prepared according to the method presentedfor the synthesis of compound 19F of Example 19 utilizing compound 110C.MS (m/z) 561.00 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(5-chloro-3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(110E)

The title compound (110E) was prepared according to the method presentedfor the synthesis of compound 10A of Example 10 utilizing compound 110Dand2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. HPLC retention time 6.63 min (2-98% acetonitrile:water with 0.1%trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18column 4.6×100 mm). MS (m/z) 807.16 [M+H]⁺.

Example 111

Synthesis ofN—((S)-1-(3-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(111)

The title compound (111) was prepared according to the method presentedfor the synthesis of compound 106E of Example 106 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and 106D. ¹H NMR (400 MHz, Methanol-d₄): δ 8.83 (d), 7.72 (d), 7.51(d), 6.98 (d), 6.64 (t), 6.58-6.44 (m), 5.41-5.18 (m), 4.74 (s),3.27-2.96 (m), 2.67-2.18 (m), 1.62 (s), 1.40 (q), 1.17-0.99 (m). MS(m/z): 747.30 [M+H]⁺

Example 112

Synthesis ofN-(1,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(112A)

The title compound (112A) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing 58D. MS (m/z)366.1 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(3-(1,4-dimethyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)carbamate(112B)

The title compound (112B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing 112A. MS (m/z) 654.4 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1,4-dimethyl-1H-indazol-3-yl)methanesulfonamide(112C)

The title compound (112C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 112B. MS (m/z) 554.2[M+H]⁺.

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(1,4-dimethyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(112D)

The title compound (112D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 112C and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 8.16-8.10 (m), 8.00 (d), 7.76 (d), 7.58(d), 7.38 (d), 7.06 (dd), 6.86 (dd), 6.67 (t), 6.64 (dt), 6.51-6.41 (m),6.38 (d), 6.24 (dd), 6.13 (dd), 5.62 (q), 5.06 (q), 4.78 (d), 4.69 (s),3.35 (s), 3.32 (s), 3.29 (s), 3.11 (s), 3.10-2.91 (m), 2.87-2.78 (m),2.55-2.34 (m), 1.71 (s), 1.45-1.34 (m), 1.20-1.07 (m) MS (m/z) 800.6[M+H]⁺.

Example 113

Synthesis of (Z)-3-bromo-2-((1,2-dichlorovinyl)oxy)benzaldehyde (113A)

Trichloroethylene (2.68 mL, 30 mmol) was added drop wise over a periodof 30 min to a solution of 3-bromo-2-hydroxybenzaldehyde (2 g, 9.9 mmol)suspended with K₂CO₃ (4.1 g, 30 mmol) in DMF (8 mL) at 60° C. under N₂.The reaction was stirred for 15 h then cooled to room temperature andpartitioned between 150 mL of ethylacetate and 100 mL of water. Theorganic phase was washed with brine 100 mL, dried over sodium sulfate,filtered and concentrated. The crude material was purified by silica gelto give the title compound.

Synthesis of 5-bromo-3-chloro-1H-benzofuro[3,2-c]pyrazolebenzaldehyde(113B)

Benzenesulfonylhydrazide (0.57 g, 3.3 mmol) was added all at once to asolution of the 113A (0.9 g, 3.0 mmol) in acetonitrile (13 mL) at roomtemperature. After stirring for 2 h, aqueous 2 M NaOH (3 mL, 6 mmol) wasadded drop wise over 10 min. The solution was heated to 50° C. andstirred for 1 h. After cooling to room temperature, the solvents wereremoved under vacuum. The residue was partitioned between 20 mL EtOAcand 15 mL H₂O. The organic layer was dried over MgSO₄, filtered andsolvent removed under vacuum yielding the title compound 113B.

Synthesis of (3-chloro-1H-benzofuro[3,2-c]pyrazol-5-yl)boronic acid(113C)

To 113B (200 mg, 0.73 mmol) in dioxane (5 mL) was addedbis(pinacolato)diboron (262 mg, 1 mmol), potassium acetate (0.144 g, 1mmol), and Pd(PPh₃)₂Cl₂ (26 mg, 0.03 mmol). The reaction mixture sealedand heated to 100° C. for 1 h. The reaction was cooled to roomtemperature and telescoped to the next reaction. MS (m/z) 237.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-chloro-1H-benzofuro[3,2-c]pyrazol-5-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(113D)

The title compound (113D) was prepared according to the method presentedfor the synthesis of compound 33F of Example 33 utilizing 113C and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.88-8.60 (m, 1H), 7.80 (d), 7.70 (d),7.51 (d), 7.35 (t), 6.44-6.17 (m), 5.50-5.27 (m), 4.80-4.74 (m),3.12-2.72 (m), 2.55-2.48 (m), 1.64 (s), 1.45-1.35 (m), 1.14-1.06 (m). MS(m/z) 772.2 [M+H]⁺.

Example 114

Synthesis of 4-methoxy-1-methyl-1H-indazol-3-amine (114B)

The title compound (114B) was prepared according to the method presentedfor the synthesis of compound 19B of Example 19 utilizing 114A. MS (m/z)178.1 [M+H]⁺.

Synthesis of 7-bromo-4-methoxy-1-methyl-1H-indazol-3-amine (114C)

A flask was charged with 114B (3.7 g, 20.9 mmol) and H₂SO₄ (35 mL) andcooled to 0° C. in an ice bath. Then NBS (1.9 g, 10 mmol) was added. Thereaction mixture was allowed to warm to room temperature and dilutedwith ice water and filtered to remove solids. The mother liquor wasbasified with saturated NaHCO₃ and extracted 2× EtOAc. The organic layerwas dried over sodium sulfate, concentrated, and purified by flashcolumn chromatography to provide the title compound. MS (m/z) 256.2[M+H]⁺.

Synthesis of4-methoxy-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(114D)

The title compound (114D) was prepared according to the method presentedfor the synthesis of compound 19C of Example 19 utilizing 114C. MS (m/z304.2 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-4-methoxy-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(114E)

The title compound (114E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing 114D. MS (m/z 592.1 [M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(3-amino-4-methoxy-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(114F)

The title compound (114F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 114E. MS (m/z) 492.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-4-methoxy-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(114G)

The title compound (114G) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 114F and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Methanol-d₄) δ: 8.72-8.62 (m), 7.66 (dd), 7.51 (dd), 7.19(d), 6.87-6.65 (m), 6.65-6.51 (m), 6.44 (d), 6.40-6.30 (m), 5.34-5.26(m), 5.11-4.99 (m), 4.79-4.71 (m), 4.02 (d), 3.28-3.22 (m), 3.14 (d),3.07 (dd), 3.02-2.90 (m), 2.83 (s), 2.53-2.35 (m), 1.63 (d), 1.38 (q),1.11-0.99 (m). MS (m/z) 738.6 [M+H]⁺.

Example 115

Synthesis of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (115A)

The title compound (115A) was prepared according to the method presentedfor the synthesis of compound 117B of Example 117 utilizing(S)-(6-bromo-2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)boronicacid (117A) and 3,3-dimethylbut-1-yne. MS (m/z): 459.22 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(115B)

The title compound (115B) was prepared according to the method presentedfor the synthesis of compound 106C of Example 106 utilizing compound115A and compound 106B. MS (m/z): 581.14 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-5-chloro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(115C)

The title compound (115C) was prepared according to the method presentedfor the synthesis of compound 37E of Example 37 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 115B. ¹H NMR (400 MHz, Methanol-d₄): δ 8.74 (d), 7.68(d), 7.45 (d), 7.03 (d), 6.69-6.62 (m), 6.65 (t), 6.59-6.45 (m),5.36-5.14 (m), 4.69 (s), 3.23-3.05 (m), 2.59-2.22 (m), 1.39 (s),1.41-1.28 (m), 1.13-0.83 (m). MS (m/z): 727.41 [M+H]⁺.

Example 116

Synthesis ofN—((S)-1-(3-(3-amino-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(116A)

In a microwave tube were charged with compound 115C (15 mg, 0.02 mmol),trimethylboroxine (9 μL, 0.06 mmol), potassium carbonate (8.5 mg, 0.06mmol) and PdCl₂[PPh₃]₂ (1.5 mg, 0.002 mmol). To the mixture was added 1mL of 1,4-dioxane and 0.1 mL of water. The mixture was heated to 160° C.for 20 minutes in a microwave synthesizer. After cooled to roomtemperature, it was partitioned between EtOAc and water. The organiclayer was separated and washed with brine, then dried over MgSO₄,filtered and concentrated. The residue was purified by reverse phaseHPLC to afford the title compound 116A. ¹H NMR (400 MHz, Methanol-d₄) δ8.82 (d), 7.67 (d), 7.47 (d), 6.87 (dd), 6.72-6.65 (m), 6.68 (t),6.58-6.45 (m), 5.26-5.11 (m), 4.70 (s), 3.25-3.05 (m), 2.99 (d),2.58-2.32 (m), 1.39 (s), 1.39-1.37 (m), 1.14-0.88 (m). MS (m/z) 707.30[M+H]⁺.

Compound 116B was obtained as a side product. MS (m/z): 693.23 [M+H]⁺.

Example 117

Synthesis of(S)-(6-bromo-2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)boronicacid (117A)

To a solution (S)-tert-butyl(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (14A)(6.2 g, 12.6 mmol) in 2-methyltetrahydrofuran (25 ml) was added dropwise1M LiHMDS in THF (12.6 ml) at 0° C. After stirring at room temperaturefor 20 minutes, the reaction was concentrated in vacuo, dissolved intoluene (30 mL), concentrated in vacuo, and re-dissolved in 2-MeTHF (25ml). To the resulting solution was added triisopropyl borate (7.11 ml,37.8 mmol) at −78° C. followed by the dropwise addition of 1Mn-butyllithium in hexanes (20 ml) over 15 minutes. After stirring for 5minutes, the reactions were gradually warmed to 0° C., and quenched with4M aqueous NH₄Cl (75 mL). Additional 2-MeTHF (25 mL) was added and theorganic layer was dried with Na₂SO₄, filtered, and concentrated invacuo. The crude product was taken to the next step without furtherpurification. MS (m/z) 456.87 [M+H]⁺.

Synthesis of(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (117B)

A solution of(S)-(6-bromo-2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)boronicacid (117A) (5.76 g, 12.6 mmol), 2-methyl-3-butyn-2-ol (2.44 ml, 25.2mmol), and triethylamine (7.0 ml, 50.4 mmol) in tetrahydrofuran (21 ml)was degassed with argon. To the reaction was added CuI (72 mg, 0.38mmol) and PdCl₂(PPh₃)₂ (2.65 g, 0.38 mmol) and the resulting mixture wasstirred at room temperature for 1 h. The reaction was concentrated invacuo and extracted with ethyl acetate and water. The organic layer wasdried with Na₂SO₄, filtered, concentrated in vacuo, and purified bysilica chromatography to give the title compound. MS (m/z) 460.11[M+H]⁺.

Synthesis of8-bromo-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine(117C)

The title compound (117C) was prepared according to the method presentedfor the synthesis of 76C in Example 76 utilizing3-bromo-2-hydrazinylpyridine and 1,1,1-trifluoro-2-isothiocyanatoethane.MS (m/z) 295.0 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)carbamate(117D)

In a microwave vial,(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (117B, 30 mg, 0.07 mmol) was combined with8-bromo-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine(117C, 19 mg, 0.07 mmol), PdCl₂(PPh₃)₂ (2 mg, 5 mol %), K₂CO₃ (65 ml of2 M aqueous solution), and LiCl (1 mg) in dioxane (1 ml). Argon wasbubbled into the reaction solution for 5 min. The reaction was heated ina microwave reactor at 155° C. for 15 min. After cooling to ambienttemperature, the reaction was partitioned between EtOAc and water. Theorganics were separated, dried, and removed in vacuo and the residue waspurified by column chromatography on silica to provide the titlecompound (117D). MS (m/z) 631.0 [M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(3-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(117E)

The title compound (117E) was prepared according to the method presentedfor the synthesis of compound 19F of Example 19 utilizing compound 117D.

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-((2,2,2-trifluoroethyl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)acetamide(117F)

The title compound (117F) was prepared according to the method presentedfor the synthesis of compound 37E of Example 37 utilizing compound 117E.¹H NMR (400 MHz, Methanol-d₄) δ 8.85 (d), 8.34 (d), 7.76 (d), 7.56 (d),7.38 (s), 7.23 (t), 6.67 (t), 6.66-6.58 (m), 6.51-6.45 (m), 5.30-5.12(m), 4.69 (s), 4.33-4.18 (m), 3.27-3.04 (m), 2.53-2.36 (m), 2.00 (d),1.43-1.26 (m), 1.03 (s). MS (m/z) 777.1 [M+H]⁺.

Example 118

Synthesis ofN—((S)-1-(3-(5-chloro-3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(118)

The title compound (118) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing compound 115C.¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (d), 7.69 (d), 7.42 (d), 7.09-6.97(m), 6.89 (d), 6.70 (t), 6.63 (t), 6.53-6.41 (m), 5.37-5.19 (m), 4.72(s), 3.22-3.00 (m), 3.11 (s), 2.56-2.35 (m), 1.39 (s), 1.39-1.33 (m),1.13-0.91 (m). MS (m/z): 805.78 [M+H]⁺.

Example 119

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(119A)

The title compound (119A) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 70 in Example 70utilizing 55A. MS (m/z) 675.0 [M+H]⁺.

Synthesis of 119B

The title compound (119B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 19F in Example 19utilizing 119A. MS (m/z) 575.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(119C)

The title compound (119C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 10A in Example 10utilizing 119B and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.76 (d), 7.68 (dd), 7.53 (dd),7.14 (q), 7.05 (d), 6.82-6.69 (m), 6.69-6.57 (m), 6.46-6.40 (m),6.40-6.30 (m), 5.33-5.21 (m), 5.05-4.92 (m), 4.81-4.76 (m), 3.52-3.43(m), 3.29-3.20 (m), 3.12 (dd), 3.06-2.92 (m), 2.60-2.40 (m), 1.49-1.31(m), 1.25 (dd), 1.17-1.03 (m). MS (m/z): 839.8 [M+H]⁺.

Example 120

Synthesis of 5-bromo-3-methylimidazo[1,5-a]pyridine (120A)

6-(Bromopyridin-2-yl)methylamine (4.0 g, 21.4 mmol) was added dropwiseto acetic anhydride (10 ml) at 0° C. The reaction was warmed to roomtemperature and to the reaction was added p-toluenesulfonic acid (4.07g, 20.4 mmol). The reaction was heated in a microwave reactor at 140° C.for 25 minutes. The reaction was concentrated in vacuo, the crudeproduct was taken up in water, pH adjusted to 9 with 1N aqueous NaOH,and extracted with twice with ethyl acetate. The organic layers weredried with Na₂SO₄, filtered, concentrated in vacuo, and purified bysilica gel chromatography to give the title compound. MS (m/z) 213.06[M+H]⁺.

Synthesis of 5-bromo-3-methyl-1-nitroimidazo[1,5-a]pyridine (120B)

To 5-bromo-3-methylimidazo[1,5-a]pyridine (120A) (3.0 g, 14.2 mmol) inacetic acid (15 ml) was added dropwise a solution of 70% HNO₃ (0.82 ml)and conc. H₂SO₄ (0.82 ml) in acetic acid (8 ml). An exotherm wasproduced during the reaction. After stirring at room temperature for 45mins, the resulting solution was added to stirring mixture of ice andbrine (150 mL). To the chilled solution was added 8M aqueous NaOH (4.3mL). The yellow precipitate was filtered and washed with water. Thecrude product was taken to the next step without further purification.MS (m/z) 255.95 [M+H]⁺.

Synthesis ofN-(5-bromo-3-methylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroacetamide(120C)

To a solution of 5-bromo-3-methyl-1-nitroimidazo[1,5-a]pyridine (120B)(0.30 g, 1.17 mmol) and trifluoroacetic acid anhydride (0.5 ml, 3.51mmol) in trifluoroacetic acid (4.2 ml) was added in portions zinc dust(0.15 g, 2.34 mmol). The reaction produces a strong exotherm. Uponcompletion, the reaction was concentrated in vacuo, and extracted withEtOAc and saturated aqueous NaHCO₃. The organic layer was dried withNa₂SO₄, filtered, concentrated in vacuo, and purified by silica gelchromatography eluting with ethyl acetate and hexanes to give the titlecompound. MS (m/z) 322.018 [M+H]⁺.

Synthesis of 5-bromo-3-methylimidazo[1,5-a]pyridin-1-amine (120D)

A solution ofN-(5-bromo-3-methylimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroacetamide(120C) (50 mg, 0.16 mmol) in 7N ammonia in methanol (1 ml) was heated ina microwave reactor at 70° C. for 30 minutes. The reaction wasconcentrated in vacuo. The resulting crude mixture was suspended inEtOAc, concentrated in vacuo, and dried under vacuum. The crude productwas taken to the next step without further purification. MS (m/z) 228.12[M+H]⁺.

Synthesis ofN-(5-bromo-3-methylimidazo[1,5-a]pyridin-1-yl)methanesulfonamide (120E)

To a solution of 5-bromo-3-methylimidazo[1,5-a]pyridin-1-amine (120D)(35 mg) and triethylamine (48 ul, 0.34 mmol) in dichloromethane (0.5 ml)was added methanesulfonyl chloride (24 μl, 0.31 mmol). After stirring atroom temperature for 30 minutes, 2M methylamine in THF (0.250 mL) wasadded, and the reaction was concentrated in vacuo. The crude product wasdissolved in 2-propanol (2.0 mL) and to the reaction was added 1.0Maqueous NaOH (2.0 mL). After stirring at room temperature for 1.5 h, thereaction was acidified with AcOH (180 uL), and the resulting mixture wasconcentrated in vacuo. The mixture was extracted with ethyl acetate andwater. The organic layers were dried with Na₂SO₄, filtered, concentratedin vacuo, and purified by silica gel chromatography to give the titlecompound. MS (m/z) 305.88 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-methyl-1-(methylsulfonamido)imidazo[1,5-a]pyridin-5-yl)pyridin-2-yl)ethyl)carbamate(120F)

A solution ofN-(5-bromo-3-methylimidazo[1,5-a]pyridin-1-yl)methanesulfonamide (120E)(50 mg, 0.16 mmol),(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (117B) (90.8 mg, 0.20 μmol), anddichlorobis(triphenylphosphine)palladium(II) (11.5 mg, 0.016 mmol) indioxane (1.2 ml) was purged with argon. To the reaction was added 1Maqueous Na₂CO₃ (0.4 ml), solution was purged with argon, and heated in amicrowave reactor for 30 mins at 120° C. To the resulting solution wasadded 5% AcOH in brine (10 mL) and was extracted twice with EtOAc. Theorganic layers were dried with Na₂SO₄, filtered, concentrated in vacuo,and purified by silica gel chromatography to give the title compound asa mixture of atropisomers. MS (m/z) 639.94 [M+H]⁺.

Synthesis of(S)—N-(5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-1-yl)methanesulfonamide(120G)

(S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-methyl-1-(methylsulfonamido)imidazo[1,5-a]pyridin-5-yl)pyridin-2-yl)ethyl)carbamate(120F) (75 mg, 0.12 mmol) was dissolved in DCM (1.0 mL) and TFA (0.5 mL)and stirred at room temperature for 30 mins. The resulting solution wasconcentrated in vacuo and extracted with ethyl acetate and saturatedaqueous NaHCO₃ followed by water. The organic layer was dried withNa₂SO₄, filtered, and concentrated in vacuo. The crude product as amixture of atropisomers was taken to the next step without furtherpurification. MS (m/z) 540.12 [M+H]⁺.

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-methyl-1-(methylsulfonamido)imidazo[1,5-a]pyridin-5-yl)pyridin-2-yl)ethyl)acetamide(120H)

The title compound (120H) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (33F) ofExample 33 utilizing(S)—N-(5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-1-yl)methanesulfonamide(120G). ¹H NMR (400 MHz, Methanol-d4) δ 8.88-8.81 (m), 8.75 (d), 7.84(dd), 7.70-7.53 (m), 6.90 (dd), 6.83-6.74 (m), 6.73-6.65 (m), 6.58 (dd),6.54-6.46 (m), 5.99 (dd), 5.31-5.22 (m), 5.01-4.92 (m), 4.74-4.61 (m),3.41-3.28 (m), 3.24-3.12 (m), 3.10-2.99 (m), 2.53-2.39 (m), 1.87 (s),1.65 (s), 1.64 (s), 1.43-1.33 (m), 1.11-1.04 (m), 1.05-0.97 (m). MS(m/z) 786.13 [M+H]⁺.

Example 121

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-methyl-1-(methylsulfonamido)imidazo[1,5-a]pyridin-5-yl)pyridin-2-yl)ethyl)acetamide(121)

The title compound (121) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (33F) ofExample 33 utilizing(S)—N-(5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-1-yl)methanesulfonamide(120G) and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.97 (d), 8.83 (d), 7.84 (dd),7.70 (dd), 7.65-7.52 (m), 6.96-6.86 (m), 6.84-6.74 (m), 6.70-6.62 (m),6.62-6.55 (m), 6.54-6.43 (m), 5.99 (dd), 5.32-5.22 (m), 5.01-4.89 (m),4.81-4.66 (m), 3.51-3.36 (m), 3.26-3.15 (m), 3.14-2.97 (m), 2.55-2.43(m), 1.88 (s), 1.65 (s), 1.64 (s), 1.46 (s), 1.45-1.36 (m), 1.13 (s),1.09-1.04 (m). MS (m/z) 804.15 [M+H]⁺.

Example 122

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(sulfamoylamino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(122)

The title compound (122) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 10A in Example 10utilizing 119B and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.91-8.81 (m), 7.69 (dd), 7.53(dd), 7.22-7.12 (m), 7.06 (d), 6.98-6.59 (m), 6.50-6.32 (m), 5.36-5.24(m), 4.99 (d), 3.34 (s), 3.24 (dd), 3.14 (dd), 3.02 (s), 2.97 (dd),2.66-2.38 (m), 1.63 (s). MS (m/z): 859.3 [M+H]⁺.

Example 123

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-((N-methylsulfamoyl)amino)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(123)

The title compound (123) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of 70 in Example 70utilizing 57 and methylsulfamoyl chloride. ¹H NMR (400 MHz, Methanol-d₄)δ 8.75-8.67 (m), 7.68 (d), 7.57-7.51 (m), 7.15 (d), 7.06 (d), 6.86-6.52(m), 6.48-6.29 (m), 5.33-5.23 (m), 4.96 (q), 4.80-4.64 (m), 3.21-3.05(m), 3.05-2.89 (m), 2.78 (s), 2.72 (s), 2.55-2.39 (m), 1.64 (s),1.48-1.28 (m), 1.11-0.95 (m). MS (m/z) 835.8 [M+H]⁺.

Example 124 Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(124)

The title compound (124) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(19F) and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid.¹H NMR (400 MHz, Methanol-d₄) 8.68 (t), 7.71 (dd), 7.54 (dd), 7.25-7.14(m), 7.11 (d), 6.80-6.73 (m), 6.69-6.60 (m), 6.53 (dd), 6.46-6.36 (m),5.29-5.22 (m), 5.04-4.96 (m), 4.91-4.75 (m), 4.72 (d), 4.67 (d), 4.17(s), 3.58 (s), 3.33 (s), 3.26 (s), 3.23 (s), 3.15 (dd), 3.04 (s),3.02-2.94 (m), 2.65-2.43 (m), 2.40-2.28 (m), 1.85-1.69 (m), 1.64 (s),1.64 (s). MS (m/z) 804.18 [M+H]⁺.

Examples 125 and 126

Synthesis of 3-chloro-4,5,6,7-tetrahydro-1H-indazole (125A)

A solution of 4,5,6,7-tetrahydro-1H-indazol-3-ol (0.41 g, 3.0 mmol) intrichlorophosphate (1.5 ml) was heated in a microwave reactor underargon at 225° C. for 15 minutes. The reaction was concentrated in vacuoand carefully quenched with 1.0N aqueous NaOH at 0° C. and extractedwith dichloromethane. The organic layer was dried with Na₂SO₄, filtered,concentrated in vacuo and purified by silica gel chromatography to givethe title compound. MS (m/z) 157.14 [M+H]⁺.

Synthesis of a 1:5 mixture of ethyl2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetate and ethyl2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate (125B)

To a solution of 3-chloro-4,5,6,7-tetrahydro-1H-indazole (125A) in DMF(1.6 ml) was added portionwise NaH (60% w mineral oil) (74.9 mg, 1.95mmol). After stirring at room temperature for 15 mins, ethylbromoacetate (0.22 ml, 1.95 mmol) was added dropwise at 0° C. Thereaction was warmed to room temperature and stirred for 2 h. Thereaction was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water. The organic layer was dried withNa₂SO₄, filtered, concentrated in vacuo and purified by silica gelchromatography to give the title compounds as a 1:5 mixture of ethyl2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetate and ethyl2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate (125B). MS (m/z)243.11 [M+H]⁺.

Synthesis of a 1:5 mixture of2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetic acid and2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (125C)

To a 1:5 mixture of ethyl2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetate and ethyl2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate (125B) (15 mg,61.8 μmol) in methanol (250 μl) was added 2M aqueous LiOH (62 μl). Thereaction was heated at 50° C. for 1.5 h. The mixture was concentrated invacuo, extracted with 2-methyltetrahydrofuran (2 mL) and 0.1N HCl (1.3mL). The organic layer was dried with Na₂SO₄, filtered, and concentratedin vacuo. The crude product was taken to the next step without furtherpurification. MS (m/z) 215.14 [M+H]⁺.

Syntheses of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetamide(125D) and of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(126)

The title compounds (125D and 126) were both prepared as mixtures ofatropisomers according to the method presented for the synthesis ofcompound 33F of Example 33 utilizing the free base form of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(19F) and 1:5 mixture of2-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetic acid and2-(3-chloro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (125C). Theregioisomers were separated by reverse phase HPLC to provide the titleproducts (125D): ¹H NMR (400 MHz, Methanol-d4) δ 8.56-8.45 (m), 7.70(dd), 7.53 (dd), 7.27-7.14 (m), 7.10 (d), 6.79-6.71 (m), 6.66-6.59 (m),6.53-6.47 (m), 6.44-6.33 (m), 5.32-5.22 (m), 5.05-4.92 (m), 4.71 (d),4.67 (s), 3.36 (s), 3.25 (s), 3.23 (s), 3.21-3.16 (m), 3.16-3.07 (m),3.03 (s), 3.01-2.90 (m), 2.64-2.53 (m), 2.44-2.30 (m), 1.76 (dd), 1.64(s), 1.64 (s). MS (m/z) 770.24 [M+H]⁺. (126): ¹H NMR (400 MHz,Methanol-d₄) δ 7.71 (dd), 7.53 (dd), 7.27-7.14 (m), 7.11 (d), 6.82-6.7(m), 6.68-6.60 (m), 6.54 (d), 6.47-6.34 (m), 5.26 (dd), 5.00 (t), 4.60(s), 4.55 (s), 3.34 (s), 3.26 (s), 3.23 (s), 3.25-3.19 (m), 3.17-3.10(m), 3.03 (s), 3.02-2.92 (m), 2.47-2.27 (m), 1.85-1.67 (m), 1.64 (s),1.64 (s). MS (m/z) 770.24 [M+H]⁺.

Example 127

Synthesis ofN—((S)-1-(6-(3-amino-3-methylbut-1-yn-1-yl)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(127)

The title compound (127) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 142 ofExample 142 utilizing 2-methylbut-3-yn-2-amine. ¹H NMR (400 MHz, cd₃od)δ 8.79 (t), 7.79 (d), 7.76 (d), 7.64 (d), 7.61 (d), 7.22-7.15 (m), 7.08(d), 6.82-6.75 (m), 6.70-6.63 (m), 6.45-6.40 (m), 6.40-6.35 (m),5.30-5.21 (m), 5.04-4.95 (m), 4.78 (s), 4.75 (d), 3.32 (s), 3.26 (s),3.23 (s), 3.20-3.13 (m), 3.06-2.95 (m), 2.94 (s), 2.50 (ddt), 1.82 (s),1.82 (s), 1.48-1.28 (m), 1.14 (dd), 1.09-1.00 (m). MS (m/z) 838.3[M+H]⁺.

Example 128

Synthesis of N1,N1-dimethyl-N2-(2-methylbut-3-yn-2-yl)ethane-1,2-diamine(128A)

Argon was bubbled through a solution of 2-methylbut-3-yn-2-yl acetate(15.96 mg, 126.5 μmol), copper chloride (0.75 mg, 7.59 μmol),triethylamine (17.63 μl, 126.5 μmol), and N,N-dimethylethylenediamine(20.73 μl, 189.74 μmol) in DMF (0.2 ml). The reaction was heated in amicrowave reactor at 110° C. for 5 min. The reaction was cooled to roomtemperature and telescoped to the next reaction.

Synthesis ofN—((S)-1-(6-(3-amino-3-methylbut-1-yn-1-yl)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(128B)

Into the reaction was added 157F (20 mg, 25.3 μmol) in DMF (0.2 mL), CuI(1 mg, 5.06 μmol), and PdCl₂(PPh₃)₂ (3.55 mg, 5.06 μmol). Argon wasbubbled through the reaction and diethylamine (39 μl, 379 μmol) wasadded. The reaction was heated in a microwave reactor for 15 mins at125° C. The excess amines were removed under vacuum and the product waspurified by reverse phase HPLC the title product 128B as a mixture ofatropisomers. ¹H NMR (400 MHz, cd₃od) δ 8.76 (t), 7.76 (d), 7.73 (d),7.64 (d), 7.61 (d), 7.21-7.16 (m), 7.07 (d), 6.82-6.74 (m), 6.69-6.62(m), 6.45-6.40 (m), 6.37 (ddd), 5.30-5.24 (m), 4.99 (dd), 4.78 (s), 4.76(d), 3.60-3.48 (m), 3.32 (s), 3.26 (s), 3.23 (s), 3.18-3.11 (m), 3.01(s), 2.97 (s), 2.58-2.42 (m), 1.77 (s), 1.48-1.37 (m), 1.13 (tt),1.10-1.03 (m). MS (m/z) 908.3 [M+H]⁺.

Example 129

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(2,3-dichlorophenyl)acetamide(129)

The title compound (129) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(2,3-dichlorophenyl)acetic acid. ¹H NMR (400 MHz,Methanol-d₄) δ 7.70 (dd), 7.53 (dd), 7.44 (dd), 7.39 (dd), 7.28-7.05(m), 6.80-6.69 (m), 6.68-6.61 (m), 6.60 (d), 6.48-6.36 (m), 5.35-5.20(m), 5.06-4.92 (m), 3.67 (s), 3.62 (s), 3.22 (s), 3.20-3.11 (m), 3.07(s), 3.00 (dd), 1.64 (s). MS (m/z) 762.3 [M+H]⁺.

Example 130

Synthesis of2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3,3-dimethylbut-1-yn-1-yl)-3-(5-methoxy-3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)acetamide(130)

To compound 115C (15 mg, 0.2 mmol) dissolved in 0.5 mL of methylenechloride was added triethylamine (37 μL, 0.2 mmol) followed bymethanesulfonyl chloride (8 μL, 0.1 mmol). The reaction mixture wasallowed to stir at room temperature for 30 minutes. The reaction wasdiluted with methylene chloride and water. The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in 1 mL of methanol and to it was added 0.1 mL of15% NaOH aqueous solution. The mixture was stirred at 40° C. forovernight then 60° C. for 7 hours. The solvent was removed and theresidue was purified by RP-HPLC to afford the title compound 130. ¹H NMR(400 MHz, Methanol-d₄) δ 7.68 (d), 7.43 (d), 7.22-7.11 (m), 6.70 (t),6.63 (t), 6.53-6.43 (m), 6.27 (d), 5.28 (t), 4.71 (s), 4.12 (s),3.26-2.89 (m), 3.18 (s), 2.52-2.40 (m), 1.40-1.31 (m), 1.39 (s),1.09-1.00 (m). MS (m/z): 801.65 [M+H]⁺.

Example 131

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(131A)

The title compound (131A) was prepared according to the method presentedfor the synthesis of compound 4F of Example 4 utilizing compound 14A and3,3-dimethylbut-1-yne. MS (m/z) 494.92 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(131B)

The title compound (131B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing compound 131A and compound 19C. MS (m/z) 594.44[M+H]⁺.

Synthesis of(S)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-amine(131C)

The title compound (131C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 105C ofExample 105 utilizing compound 131B. MS (m/z) 494.26 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(131D)

The title compound 131D was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 37E ofExample 37 utilizing2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 131C. MS (m/z) 740.35 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3,3-dimethylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(131E)

The title compound (131E) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing compound 131D.¹H NMR (400 MHz, Methanol-d₄) δ 7.67-7.63 (m), 7.49-7.44 (m), 7.17 (d),7.06 (d), 6.90-6.47 (m), 6.79 (t), 6.47-6.20 (m), 5.33-5.23 (m), 4.95(t), 4.79-4.49 (m), 3.33 (s), 3.24 (d), 3.13 (dd), 3.05-2.83 (m), 3.00(s), 2.58-2.14 (m), 1.43-1.31 (m), 1.41 (s), 1.13-0.93 (m). MS (m/z):818.15 [M+H]⁺.

Example 132

Synthesis of 7-bromo-4-fluoro-1-methyl-1H-indazol-3-amine (132A)

A solution of 4-fluoro-1-methyl-1H-indazol-3-amine (4.3 g, 26 mmol) inconcentrated sulfuric acid (26 ml) was cooled to 0° C. then treated inthree portions with N-bromosuccinimide (4.64 g, 26 mmol). The reactionwas allowed to slowly reach room temperature and stirred for 15 h. Thereaction was carefully quenched with water, filtered, and the filtratewas neutralized. The neutralized solution was then extracted with ethylacetate, dried over sodium sulfate, filtered and concentrated. The crudematerial was purified by silica gel chromatography to give the titlecompound. MS (m/z) 246.1[M+H]⁺.

Synthesis ofN-(7-bromo-4-fluoro-1-methyl-1H-indazol-3-yl)methanesulfonamide (132B)

The title compound was prepared similarly to 108B of Example 108starting from 132A. MS (m/z) 320.3 [M−H]⁻.

Synthesis of2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-fluoro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)ethyl)acetamide(132C)

The title compound (132C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 117F ofExample 117 utilizing 132B, 117B and2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, cd₃od) δ 8.80-8.75 (m), 7.70 (d), 7.65-7.59 (m),7.52 (d), 7.35-7.30 (m), 7.22-7.17 (m), 7.11-7.06 (m), 6.75-6.70 (m),6.49-6.44 (m), 6.23-6.16 (m), 5.52-5.47 (m), 5.00-4.95 (m), 4.86 (d),3.26 (t), 3.02-2.97 (m), 2.52-2.47 (m), 1.63 (s), 1.45-1.36 (m),1.33-1.27 (m), 1.15-1.10 (m). MS (m/z) 822.1 [M+H]⁺.

Example 133

Synthesis of2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3,3-dimethylbut-1-yn-1-yl)-3-(5-methyl-3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)acetamide(133)

The title compound (133) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing compound 116A.¹H NMR (400 MHz, Methanol-d₄): δ 7.66 (d), 7.41 (dd), 7.02-6.90 (m),6.71 (t), 6.63 (t), 6.56-6.37 (m), 5.41-5.23 (m), 4.74 (d), 3.23-2.75(m), 3.06 (s), 2.92 (s), 2.46 (ddd), 1.45-1.32 (m), 1.39 (s), 1.11-1.01(m). MS (m/z): 785.31 [M+H]⁺.

Example 134

Synthesis of2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3,3-dimethylbut-1-yn-1-yl)-3-(3-(methylsulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)pyridin-2-yl)ethyl)acetamide(134)

The title compound (134) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing compound 116B.¹H NMR (400 MHz, Methanol-d₄) δ 8.69 (d), 8.04 (dd), 7.71 (d), 7.43 (d),7.21-7.12 (m), 6.91 (t), 6.70 (t), 6.62 (t), 6.50-6.41 (m), 5.41-5.26(m), 4.74 (s), 3.25-3.10 (m), 3.06 (s), 2.55-2.36 (m), 1.43-1.21 (m),1.40 (s), 1.14-0.96 (m). MS (m/z): 771.12 [M+H]⁺.

Example 135

Synthesis ofN—((S)-1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(135A)

The title compound (135A) may be prepared analogously to the methodpresented for the synthesis of compound 139A of Example 139 utilizing2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 182H. MS (m/z): 853.26 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methoxypyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(135B)

To a solution of compound 135A (25 mg, 0.029 mmol) in MeOH (1 mL) wasadded t-butyl nitrite (15 mg, 0.15 mmol). The resulting solution washeated at 50° C. for 2 h. The volatiles were removed in vacuo andresidue was purified by reverse phase HPLC to yield the title compoundas a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (dd),7.69 (dd), 7.53 (dd), 7.34 (d), 7.22-7.10 (m), 7.05 (dd), 6.76 (t),6.52-6.23 (m), 4.82-4.67 (m), 3.87 (d), 3.37 (s), 3.24 (d), 3.17-3.04(m), 2.97 (q), 2.49 (s), 1.71-1.55 (m), 1.49-1.31 (m), 1.07 (s). MS(m/z) 868.24 [M+H]⁺.

Examples 136

Synthesis of 7-bromo-4-chloro-1-methyl-1H-indazole (136A)

Compound 19B (150 mg, 0.58 mmol) was dissolved in Me-THF and treatedwith tert-butyl nitrite (0.21 ml, 1.73 mmol). The reaction was heated to75° C. for 2 h. The reaction was diluted with EtOAc and saturatedaqueous NaCl. The organics were separated, dried, and removed in vacuoand the residue was purified by column chromatography on silica toprovide the title compound (136A). MS (m/z) 247.0 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-1H-indazol-7-yl)-6-ethynylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(136B)

In a microwave vial,(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (117B, 35 mg, 0.08 mmol) was combined with7-bromo-4-chloro-1-methyl-1H-indazole (136A, 19 mg, 0.08 mmol),PdCl₂(PCy₃)₂ (6 mg), and NaHCO₃ (228 μl of 1 M aqueous solution) indioxane (1 ml). Argon was bubbled into the reaction solution for 5 min.The reaction was heated in a microwave reactor at 155° C. for 15 min.After cooling to ambient temperature, the reaction was partitionedbetween EtOAc and water. The organics were separated, dried, and removedin vacuo and the residue was purified by column chromatography on silicato provide the title compound (136B). MS (m/z) 523.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-1H-indazol-7-yl)-6-ethynylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(136C)

The title compound (136C) was prepared according to the method presentedfor the synthesis of compound 19F of Example 19 utilizing compound 136B.MS (m/z): 423.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-1H-indazol-7-yl)-6-ethynylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(136D)

The title compound (136D) was prepared according to the method presentedfor the synthesis of compound 10A of Example 10 utilizing compound 136Cand2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (d), 8.23 (s), 7.87 (t), 7.66(dd), 7.43 (d), 7.29 (d), 7.07-6.99 (m), 6.98-6.96 (m), 6.94 (t),5.25-5.11 (m), 4.90-4.62 (m), 3.27-2.97 (m), 2.61-2.49 (m), 1.44-1.30(m), 0.95-0.84 (m). MS (m/z): 669.1 [M+H]⁺.

Example 137

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-1H-indazol-7-yl)-6-ethynylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(137A)

In a microwave vial,(S)-(2-(1-((tert-butoxycarbonyl)amino)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)boronicacid (117B, 35 mg, 0.08 mmol) was combined with7-bromo-4-chloro-1-methyl-1H-indazole (136A, 19 mg, 0.08 mmol),PdCl₂(PPh₃)₂ (5 mg), and K₂CO₃ (95 μl of 2 M aqueous solution) indioxane (1 ml). Argon was bubbled into the reaction solution for 5 min.The reaction was heated in a microwave reactor at 115° C. for 15 min.After cooling to ambient temperature, the reaction was partitionedbetween EtOAc and water. The organics were separated, dried, and removedin vacuo and the residue was purified by column chromatography on silicato provide the title compound as a mixture of atropisomers. MS (m/z)581.0 [M+H]⁺.

Synthesis of(S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(4-chloro-1-methyl-1H-indazol-7-yl)pyridin-2-yl)-2-methylbut-3-yn-2-ol(137B)

The title compound (137B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing compound 137A. MS (m/z): 481.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(137C)

The title compound (137C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing compound 137B and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.75-8.70 (m), 8.70-8.62 (m),8.10-8.05 (m), 7.69 (dd), 7.53 (dd), 7.18 (s), 7.08 (d), 6.89-6.52 (m),6.42 (d), 6.39-6.30 (m), 5.31-5.20 (m), 5.04-4.91 (m), 4.70 (d), 3.48(t), 3.40 (s), 3.19-3.07 (m), 3.04 (s), 2.96 (dd), 2.54-2.38 (m), 1.64(d), 1.44-1.27 (m), 1.14-0.96 (m). MS (m/z): 727.1 [M+H]⁺.

Example 138

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-1-(3-(3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(138)

The title compound (138) was prepared according to the method presentedfor the synthesis of compound 106E of Example 106 utilizing compound117B and8-bromo-5-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. ¹HNMR (400 MHz, Methanol-d₄) δ 8.61 (dd), 7.78 (dd), 7.55 (d), 7.48 (t),7.46-7.37 (m), 7.33-7.18 (m), 6.83-6.74 (m), 6.67 (t), 6.62-6.47 (m),6.46-6.35 (m), 5.38-5.03 (m), 4.75-4.57 (m), 3.26-3.17 (m), 3.17-2.98(m), 2.44 (ddd), 1.61 (d), 1.42-1.30 (m), 1.06-0.96 (m, 1H). MS (m/z):730.22 [M+H]⁺.

Example 139

Synthesis ofN—((S)-1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(139A)

The title compound (139A) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19G ofExample 19 utilizing compound 182H. MS (m/z): 835.67 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methoxypyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(139B)

The title compound (139B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 135A ofExample 135 utilizing compound 139A. ¹H NMR (400 MHz, Methanol-d₄) δ8.62 (t), 7.75-7.47 (m), 7.34 (d), 7.21-6.96 (m), 6.90-6.64 (m),6.53-6.21 (m), 4.78-4.60 (m), 3.86 (d), 3.36 (s), 3.24 (d), 3.15-3.07(m), 3.01-2.90 (m), 2.61-2.35 (m), 1.64 (d), 1.37 (q), 1.28 (d), 1.03(d). MS (m/z) 850.52 [M+H]⁺.

Example 140

Synthesis oftert-butyl(((1R,2S,3R,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-yl)oxy)dimethylsilane(140A)

To a solution of(1R,2S,3R,5R)-3-((tert-butyldimethylsilyl)oxy)bicyclo[3.1.0]hexan-2-ol(10.4 g, 45.6 mmol, synthesis previous reported in JACS, 2007, 129,4456-4462), DIPEA (31.7 ml, 182.4 mmol), and DMAP (556 mg, 4.56 mmol) indichloromethane (90 mL) was added chloromethyl methyl ether (14.6 ml,182.4 mmol) at 0° C. The mixture was warmed to room temperature andstirred overnight. The resulting solution was concentrated in vacuo andextracted twice with EtOAc and water. The combined organic layers weredried over MgSO₄, filtered, and concentrated in vacuo. The crude productwas taken to next step without further purification. ¹H NMR (400 MHz,Chloroform-d) δ 4.09-3.99 (m, 1H), 2.50-2.38 (m, 1H), 2.05-1.96 (m, 2H),1.84-1.76 (m, 1H), 1.57 (s, 1H), 1.31-1.14 (m, 2H), 1.06-0.99 (m, 1H),0.95-0.81 (m, 10H), 0.07 (dd, 6H).

Synthesis of (1R,2S,3R,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-ol(140B)

To a crude solution oftert-butyl(((1R,2S,3R,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-yl)oxy)dimethylsilane(140A) (12.4 g) in THF (100 ml) was added 1M tetrabutylammonium fluoridein THF (64 mL). After stirring at room temperature for 2 h, the mixturewas partially concentrated in vacuo, and extracted twice with EtOAc andwater. The combined organic layers were washed with brine, dried withMgSO₄, filtered, and concentrated in vacuo. The resulting mixture wasslurried in 25% EtOAc and hexanes, solids filtered, and the filtrate waspurified by silica gel chromatography to give the title compound. ¹H NMR(400 MHz, Chloroform-d) δ 4.85-4.73 (m, 2H), 4.01-3.92 (m, 1H),3.87-3.74 (m, 1H), 3.47-3.41 (m, 3H), 2.16-2.06 (m, 1H), 1.73-1.61 (m,1H), 1.52-1.35 (m, 2H), 0.53-0.42 (m, 1H), 0.19-0.11 (m, 1H).

Synthesis of (1R,2S,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-one(140C)

To a mixture of (1R,2S,3R,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-ol(140B) (5.8 g, 36.7 mmol) and NaHCO₃ (4.62 g, 55.1 mmol) indichloromethane (75 ml) was added in portions Dess-Martin periodinane(17.1 g, 40.37 mmol) at −15° C. The mixture was slowly warmed to roomtemperature and stirred for 1 h. Upon completion, the reaction wascooled to 0° C. and 1M aqueous NaHCO₃ (150 ml) was added. The solutionwas stirred until evolution of gas ceased, and the organic layer wasseparated. The aqueous layer was back extracted twice withdichloromethane, the organic layers were combined, dried with Na₂SO₄,filtered, and concentrated in vacuo. The resulting mixture was slurriedin 25% Et₂O and hexanes, solids filtered, and the filtrate wasconcentrated in vacuo then, purified by silica gel chromatography togive the title compound. ¹H NMR (400 MHz, Chloroform-d) δ 4.89-4.62 (m,2H), 3.66 (s, 1H), 3.45-3.35 (m, 3H), 2.81-2.69 (m, 1H), 2.19-2.08 (m,1H), 1.73-1.54 (m, 2H), 1.03-0.92 (m, 1H), −0.00-−0.11 (m, 1H).

Synthesis of (3b-S,4aR)-ethyl5-(methoxymethoxy)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140D)

To a solution of (1R,2S,5R)-2-(methoxymethoxy)bicyclo[3.1.0]hexan-3-one(140C) (4.4 g, 28.2 mmol) in ethanol (28 ml) was added a solution of 21%NaOEt in EtOH (11.0 ml, 29.6 mmol) at 0° C. After stirring at roomtemperature for 5 minutes, diethyl oxalate (4.02 ml, 29.6 mmol) wasadded, and the reaction was stirred at 70° C. for 45 minutes. Uponcompletion, the mixture was concentrated in vacuo, dissolved in aceticacid (15 ml) and water (2 ml), and hydrazine hydrate (2.82 g, 56.4 mmol)was slowly added at 0° C. The reaction was heated in a microwave reactorat 120° C. for 10 minutes. The mixture was concentrated in vacuo andextracted with twice with 2-methyltetrahydrofuran and water. The organiclayers were combined and washed with water. The organic layer was driedwith Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography to give the title compound. MS (m/z) 252.84 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl5-hydroxy-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140E)

A solution of (3b-S,4aR)-ethyl5-(methoxymethoxy)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140D) (1.2 g, 4.76 mmol) in 1:1 AcOH:H₂O (5 ml) was heated in amicrowave reactor at 130° C. for 10 minutes. The resulting mixture wasconcentrated in vacuo and extracted with three times with EtOAc andwater. The combined organic layers were dried with Na₂SO₄, filtered,concentrated in vacuo, and partially purified by silica gelchromatography eluting with ethyl acetate and hexanes. MS (m/z) 208.98[M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl2-(2-(tert-butoxy)-2-oxoethyl)-5-hydroxy-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140F)

To a solution of (3b-S,4aR)-ethyl5-hydroxy-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140E) (990 mg) in DMF (10 ml) was added cesium carbonate (2.32 g, 7.14mmol) followed by tert-butyl bromoacetate (0.70 ml, 4.76 mmol). Afterheating the reaction at 45° C. for 1 h, the resulting mixture wasextracted with EtOAc and water. The organic layer was dried with Na₂SO₄,filtered, concentrated in vacuo, and purified by silica gelchromatography to give the title compound. MS (m/z) 322.83 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl2-(2-(tert-butoxy)-2-oxoethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140G)

To a solution of (3b-S,4aR)-ethyl2-(2-(tert-butoxy)-2-oxoethyl)-5-hydroxy-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140F) (0.27 g, 0.83 mmol) in DCM (10 ml) was added Dess Martinperiodinane (0.34 g, 0.91 mmol). After stirring at room temperature for3 h, mixture was solid loaded onto silica gel and purified by silica gelchromatography to give the title compound. MS (m/z) 320.74 [M+H]⁺.

Synthesis of sodium(3bS,4aR)-2-(2-(tert-butoxy)-2-oxoethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140H)

To a solution of (3b-S,4aR)-ethyl2-(2-(tert-butoxy)-2-oxoethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140G) (0.22 g, 0.69 mmol) in THF (2 ml) was added 0.25M aqueous NaOH(1.87 ml). The reaction was heated at 60° C. for 1.5 h. Upon completion,the reaction was concentrated in vacuo, and dried under vacuum. Thecrude product was taken to next step without further purification. MS(m/z) 291.04 [M−H]—.

Synthesis of tert-butyl2-((3bS,4aR)-3-amino-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(140I)

The title compound (140I) was prepared according to the method presentedfor the synthesis of compound (148B) of Example 148 utilizing sodium(3bS,4aR)-2-(2-(tert-butoxy)-2-oxoethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140H). MS (m/z) 263.86 [M+H]⁺.

Synthesis of tert-butyl2-((3bS,4aR)-3-chloro-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(140J)

The title compound (140J) was prepared according to the method presentedfor the synthesis of compound (149) of Example 149 utilizing tert-butyl2-((3bS,4aR)-3-amino-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(140I). MS (m/z) 282.73 [M+H]⁺.

Synthesis of2-((3bS,4aR)-3-chloro-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-2(3bH)-yl)aceticacid (140K)

To a solution of tert-butyl2-((3bS,4aR)-3-chloro-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(140J) (19 mg, 0.07 mmol), 1,2-ethanedithiol (11.3 μl, 0.13 mmol), andacetic acid (19.2 μl, 0.34 mmol) in dichloromethane (400 μl) was addedboron trifluoride diethyl etherate (20.7 μl, 0.17 mmol). After stirringat room temperature for 2 h, the mixture was dry loaded onto silica andpurified by silica gel chromatography to give the title compound as apartially purified product. MS (m/z) 302.93 [M+H]⁺.

Synthesis of2-((3bS,4aR)-3-chloro-5,5-difluoro-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)aceticacid (140L)

To a solution of N-iodosuccinimide (27.9 mg, 0.12 mmol) indichloromethane (0.10 ml) was added dropwise 70% HF in pyridine (0.10ml) at −78° C. After stirring for 15 minutes, a suspension of 140K (15mg, 0.05 mmol) in dichloromethane (0.10 ml) was added and the reactionwas gradually warmed to 0° C. over 1 h. The mixture was extracted with2-methyltetrahydrofuran and water. The organic layer was washed withbrine, dried with Na₂SO₄, filtered, and concentrated in vacuo. Theproduct was purified by preparative TLC eluting to give the titlecompound. MS (m/z) 249.05 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-chloro-5,5-difluoro-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetamide(140M)

The title compound (140M) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound (33F) ofExample 33 utilizing 19F and2-((3bS,4aR)-3-chloro-5,5-difluoro-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)aceticacid (140L). ¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (t), 7.71 (dd), 7.54(dd), 7.27-7.15 (m), 7.10 (d), 6.81-6.72 (m), 6.69-6.59 (m), 6.50 (d),6.46-6.36 (m), 5.30-5.21 (m), 5.05-4.95 (m), 4.81 (s), 4.77 (s), 3.35(s), 3.26 (s), 3.28-3.21 (m), 3.23 (s), 3.19-3.12 (m), 3.03 (s),3.04-2.97 (m), 2.45-2.32 (m), 1.94 (s), 1.64 (s), 1.64 (s), 1.42-1.25(m), 1.01-0.96 (m), 0.96-0.92 (m). MS (m/z) 804.14[M+H]⁺.

Example 141

Synthesis ofN-(7-bromo-4-methoxy-1-methyl-1H-indazol-3-yl)methanesulfonamide (141A)

The title compound (141A) was prepared according to the method presentedfor the synthesis of compound 19D of Example 19 utilizing 114C. MS (m/z)334.1 [M+H]⁺.

Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(4-methoxy-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)carbamate(141B)

In a microwave vial, (117B, 30 mg, 0.07 mmol) was combined with (141A,65 mg, 0.2 mmol), PdCl₂(PPh₃)₂ (5 mg, 0.007 mmol), and K₂CO₃ (0.2 ml of2 M aqueous solution) in dioxane (1.5 ml) and DMF (0.1 ml). Nitrogen wasbubbled into the reaction solution for 5 min. The reaction was heated ina microwave reactor at 120° C. for 15 min. After cooling to ambienttemperature, the reaction was partitioned between EtOAc and brine. Theorganics were separated, dried, and removed in vacuo and the residue waspurified by column chromatography on silica to provide the titlecompound as a mixture of atropisomers. MS (m/z) 670.3 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-methoxy-1-methyl-1H-indazol-3-yl)methanesulfonamide(141C)

The title compound (141C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 141B. MS (m/z) 570.1 [M+H]⁺.

Synthesis of2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(4-methoxy-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide(141D)

The title compound (141D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 141C and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.91-7.84 (m), 7.64 (dd), 7.54-7.42 (m),7.34-7.28 (m), 6.70 (t), 6.68-6.61 (m), 6.55-6.53 (m), 6.52-6.44 (m),6.30-6.24 (m), 6.24-6.15 (m), 5.74-5.66 (m), 5.12-5.01 (m), 4.78 (d),4.71 (d), 4.03 (s), 3.99 (s), 3.39 (d), 3.25 (s), 3.07 (s), 3.06-2.91(m), 2.81-2.54 (m), 2.54-2.36 (m), 1.71 (s), 1.41 (dd), 1.30-1.22 (m),1.22-1.10 (m). MS (m/z) 816.5 [M+H]⁺.

Example 142

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((S)-3-hydroxybut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(142)

To the reaction vial containing 168A (20 mg, 0.027 mmol) in DMF (1 mL)was added (S)-but-3-yn-2-ol (0.012 mL, 0.13 mmol), PdCl₂[P(Ph)₃]₂ (1.9mg, 0.003 mmol), and diethylamine (0.02 mL, 0.27 mmol). The reactionmixture was flushed with argon gas for 5 min then sealed and heated in amicrowave reactor to 125° C. for 20 min. Upon cooling, the reactionmixture was filtered and purified by reverse phase HPLC, to provide thetitle compound 142 as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od)1H NMR (400 MHz, cd3od) δ 8.62 (dd), 7.70 (dd), 7.54 (dd), 7.16 (s),7.07 (d), 6.88-6.52 (m), 6.44-6.33 (m), 5.31-5.23 (m), 5.02-4.92 (m),4.82-4.64 (m), 3.33 (s), 3.24 (d), 3.18-3.08 (m), 3.04-2.91 (m),2.53-2.39 (m), 1.57 (dd), 1.42-1.32 (m), 1.11-1.08 (m), 1.07-0.99 (m).MS (m/z) 806.1 [M+H]⁺.

Example 143

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((R)-3-hydroxybut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(143)

The title compound (143) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 142 ofExample 142 utilizing (R)-but-3-yn-2-ol. ¹H NMR (400 MHz, cd₃od) δ 8.63(dd), 7.70 (dd), 7.54 (dd), 7.16 (s), 7.06 (d), 6.88-6.52 (m), 6.44-6.33(m), 5.30-5.25 (m), 5.02-4.92 (m), 4.83-4.64 (m), 3.33 (s), 3.24 (d),3.18-3.08 (m), 3.04-2.91 (m), 2.50-2.39 (m), 1.57 (dd), 1.38 (m), 1.05(s), 1.03 (s). MS (m/z) 806.1 [M+H]⁺.

Example 144

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4-fluoro-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(144)

The title compound (144) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 142 ofExample 142 utilizing 1-fluoro-2-methylbut-3-yn-2-ol. ¹H NMR (400 MHz,cd₃od) δ 8.69 (t), 7.71 (dd), 7.56 (dd), 7.17 (s), 7.07 (d), 6.87-6.52(m), 6.44-6.34 (m), 5.33-5.23 (m), 5.03-4.94 (m), 4.78-4.63 (m), 4.50(d), 4.38 (d), 3.24 (d), 3.19-3.08 (m), 3.05-2.92 (m), 2.44 (ddd), 1.63(dd), 1.39 (dd), 1.08 (s), 1.02 (s). MS (m/z) 839.1 [M+H]⁺.

Example 145

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxypent-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(145)

To the reaction vial containing 157F (20 mg, 0.025 mmol) in DMF (1 mL)was added pent-1-yn-3-ol (0.011 g, 0.13 mmol), Pd(PPh₃)₂Cl₂ (1.7 mg,0.003 mmol), and diethylamine (0.02 mL, 0.25 mmol). The reaction mixturewas flushed with argon gas for 5 min then sealed and heated in amicrowave reactor to 125° C. for 20 min. Upon cooling, the reactionmixture was filtered and purified by reverse phase HPLC the titlecompound 145 as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ8.72 (dd), 7.70 (dd), 7.54 (dd), 7.16 (d), 7.06 (d), 6.81-6.71 (m),6.66-6.59 (m), 6.46-6.34 (m), 5.35-5.20 (m), 5.03-4.93 (m), 4.81-4.70(m), 4.61-4.52 (m), 3.34 (s), 3.24 (d), 3.20-3.11 (m), 3.05-2.93 (m),2.52-2.43 (m), 1.96-1.79 (m), 1.41 (dt), 1.13 (td). MS (m/z) 840.0[M+H]⁺.

Example 146

Synthesis of 3,5-dichloro-N-methoxy-N-methylpyrazine-2-carboxamide(146B)

To a solution of 146A (10 g, 51.82 mmol) and HATU (21.67 g, 57 mmol) inDMF (50 mL), DIEA (19.86 mL, 114 mmol) was added to the solution. After30 minutes, N,O-dimethylhydroxyamine hydrochloride (6.09 g, 62.18 mmol)was added to the solution. The mixture was stirred for overnight. 300 mLof water was added and extracted with EtOAc three times (100 mL). Thecrude product was purified by flash column to provide the desiredproduct. MS (m/z) 236 [M+H]⁺.

Synthesis of3-chloro-N-methoxy-N-methyl-5-(methylthio)pyrazine-2-carboxamide (146C)

To a solution of 146B (2 g, 8.47 mmol) in DMF (10 mL), 1 eq. of sodiummethanethiolate was added to the solution. After 5 hours, 0.5 eq. ofsodium methanethiolate was added to the suspension. The reaction wasstirred overnight then diluted with EtOAc and washed with NaHCO₃(aq) andbrine. The organic layer was concentrated and purified by flash columnto provide the title compound. MS (m/z) 248 [M+H]⁺.

Synthesis of 3-chloro-5-(methylthio)pyrazine-2-carbaldehyde (146D)

To a solution of 146C (750 mg, 3.03 mmol) in THF at −78° C., DIBAL-H(3.33 mL, 3.33 mmol) in toluene was added to the solution slowly. Then,it was stirred for 2 hours at −78° C. 4 mL of 1 N HCl(aq) was added tothe solution and warmed to 0° C. The mixture was stirred for 20 minutesat 0° C. then extracted with EtOAc twice. The organic layer was driedand concentrated and used without further purification. MS (m/z) 189[M+H]⁺.

Synthesis of(S,Z)—N-((3-chloro-5-(methylthio)pyrazin-2-yl)methylene)-2-methylpropane-2-sulfinamide(146E)

The title compound (146E) was prepared according to the method presentedfor the synthesis of compound 21C of Example 21 utilizing 146D. MS (m/z)292 [M+H]⁺.

Synthesis of(S)—N—((S)-1-(3-chloro-5-(methylthio)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(146F)

The title compound (146F) was prepared according to the method presentedfor the synthesis of compound 182D of Example 182 utilizing 146E. MS(m/z) 420 [M+H]⁺.

Synthesis of(S)-1-(3-chloro-5-(methylthio)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (146G)

The title compound (146G) was prepared according to the method presentedfor the synthesis of compound 21E of Example 21 utilizing 146F. MS (m/z)316 [M+H]⁺.

Synthesis ofN—((S)-1-(3-chloro-5-(methylthio)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(146H)

The title compound (146H) was prepared according to the method presentedfor the synthesis of compound 10A of Example 10 utilizing 146G and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. MS (m/z) 562 [M+H]⁺.

Synthesis ofN—((S)-1-(3,5-bis(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(146I)

The title compound (146I) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing 33B and 146H. ¹H NMR (400 MHz, Methanol-d4) δ 9.15(d), 8.91 (s), 7.93 (t), 7.63 (d), 7.35-7.25 (m), 7.23-7.1 (m),6.85-6.75 (m), 6.74-6.6 (m), 6.6-6.50 (m), 6.4-6.32 (m), 5.75-5.6 (m),5.10-5.25 (m), 4.71 (s), 3.65 (s), 3.56 (s), 3.10-3.25 (m), 2.92 (s),2.60-2.40 (m), 1.45-1.30 (m), 1.1-0.80 (m). MS (m/z) 928 [M+H]⁺.

Example 147

Synthesis of(3bS,4aR)-1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylicacid (147)

A solution of 158G (0.41 g, 0.49 mmol) in THF (0.5 ml) was treated with1M NaOH (2 ml). The reaction was stirred at room temperature for 1.5 h.The solution was acidified to pH=4 with AcOH and extracted with 2-MeTHF(2×5 mL) and water (5 mL). The organics were dried with Na₂SO₄,filtered, and concentrated. The crude material was purified by reversephase HPLC to provide the product 147 as a mixture of atropisomers. ¹HNMR (400 MHz, cd₃od) δ, 8.69 (d), 7.69 (d), 7.53 (dd), 7.19 (d), 7.06(d), 6.81-6.71 (m), 6.63 (t), 6.46-6.35 (m), 5.32-5.23 (m), 5.03-4.93(m), 4.85-4.80 (m), 4.72 (s), 3.36 (s), 3.26 (s), 3.23 (s), 3.22-3.09(m), 3.05-2.92 (m), 2.63-2.51 (m), 2.50-2.39 (m), 1.65 (s), 1.64 (s),1.49-1.35 (m), 1.15-1.07 (m), 1.08-0.97 (m). MS (m/z) 814.1 [M+H]⁺.

Example 148

Synthesis of sodium(3bS,4aR)-1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(148A)

To a solution of 158G (0.22 g, 0.26 mmol) in THF (0.65 ml) was added 1MNaOH (0.65 ml). The reaction was stirred at room temperature for 1.5 h.The solution was acidified to ˜pH=4 with AcOH and extracted with 2-MeTHF(2×5 mL) and brine (5 mL). The organic layer was washed with NaHCO₃ (10mL). The organics were dried with Na₂SO₄, filtered, and concentrated.The product was taken to the next step without further purification. MS(m/z) 814.1 [M+H]⁺.

Synthesis of2-((3bS,4aR)-3-amino-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(148B)

To a solution of 148A (110 mg, 0.13 mmol) in DMF (1.0 ml) was addeddiphenyl phosphoryl azide (28.35 μl, 0.13 mmol). The reaction wasstirred at room temperature for 45 min. The solution was cooled to 0° C.and water (0.75 mL) was added dropwise. The resulting solution wassealed and heated in microwave reactor at 130° C. for 15 min. The crudematerial treated with TFA (20 μl) and purified by prep HPLC to providethe product 148B as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ8.72-8.59 (m), 7.75-7.65 (m), 7.53 (dd), 7.22-7.15 (m), 7.09 (d),6.83-6.72 (m), 6.67-6.60 (m), 6.46-6.33 (m), 5.28 (dd), 4.96 (t),4.90-4.70 (m), 4.69-4.52 (m), 3.35 (s), 3.26 (s), 3.25-3.22 (m), 3.20(s), 3.17-3.10 (m), 3.04-2.91 (m), 2.51-2.33 (m), 1.65 (s), 1.47-1.31(m), 1.15-1.06 (m), 1.03 (m). MS (m/z) 785.2 [M+H]⁺.

Example 149

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-chloro-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(149)

A solution of 148B (19.1 mg, 0.02 mmol), ground lithium chloride (5.16mg, 0.12 mmol), and cupric chloride (6.54 mg, 0.05 mmol) in ACN (1 ml)was sonicated for 5 min. Isoamyl nitrite (6.51 μl, 0.05 mmol) was addedand the reaction was sonicated for an additional 5 min then stirred for45 min. The crude material was purified by prep HPLC to provide thedesired product 149 as a mixture of atropisomers. ¹H NMR (400 MHz,cd₃od) δ 8.67 (d), 8.62 (d), 7.69 (dd), 7.53 (dd), 7.19 (s), 7.07 (d),6.82-6.72 (m), 6.68-6.58 (m), 6.47-6.32 (m), 5.27 (m), 5.03-4.92 (m),4.69-4.67 (m), 4.64 (d), 3.34 (s), 3.26 (s), 3.24 (s), 3.18-3.08 (m),3.05-2.92 (m), 2.53-2.30 (m), 1.64 (s), 1.45-1.27 (m), 1.13-1.07 (m),1.08-1.01 (m). MS (m/z) 804.1 [M+H]⁺.

Example 150

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(150)

To a solution of 148B (10 mg, 0.01 mmol) in ACN (0.2 ml) and 50%hypophosphorus acid in water (50 μl) was added isoamyl nitrite (3.41 μl,0.03 mmol). The reaction mixture was stirred at room temperature for 30min. The crude material was purified by prep HPLC to provide the titleproduct 150 as a mixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ 8.48(d), 8.41 (d), 7.74-7.63 (m), 7.54 (d), 7.51 (d), 7.34 (s), 7.31 (s),7.17 (s), 7.07 (d), 6.81-6.72 (m), 6.66-6.58 (m), 6.45-6.33 (m),5.34-5.26 (m), 5.02-4.93 (m), 4.74 (d), 4.69 (d), 3.33 (s), 3.26 (s),3.24 (s), 3.14-3.06 (m), 3.03-2.91 (m), 2.46-2.33 (m), 1.65 (s),1.39-1.28 (m), 1.03 (s), 1.00-0.93 (m). MS (m/z) 770.1 [M+H]⁺.

Example 151

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3,4-dihydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(151)

The title compound (151) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 145 ofExample 145 utilizing 2-methylbut-3-yne-1,2-diol. ¹H NMR (400 MHz,cd₃od) δ 8.78 (d), 7.70 (dd), 7.62-7.52 (m), 7.16 (s), 7.05 (d),6.81-6.72 (m), 6.65-6.60 (m), 6.44-6.30 (m), 5.28 (d), 4.97 (d),4.84-4.70 (m), 3.66 (d), 3.33 (s), 3.24 (d), 3.14 (dd), 3.07-2.92 (m),2.86 (s), 2.53-2.42 (m), 1.59 (d), 1.47-1.36 (m), 1.29 (t), 1.19-1.10(m), 1.09-1.04 (m). MS (m/z) 854.1 [M+H]⁺.

Example 152

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4-fluoro-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(152)

The title compound (152) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 145 ofExample 145 utilizing 1-fluoro-2-methylbut-3-yn-2-ol. ¹H NMR (400 MHz,cd₃od) δ 7.71 (dd), 7.64-7.51 (m), 7.22-7.12 (m), 7.06 (d), 6.81-6.71(m), 6.68-6.58 (m), 6.44-6.33 (m), 5.30-5.21 (m), 4.98 (t), 4.85-4.70(m), 4.50 (d), 4.38 (d), 3.24 (d), 3.20-3.11 (m), 3.06-2.93 (m),2.56-2.43 (m), 1.62 (s), 1.47-1.27 (m), 1.16-1.10 (m), 1.09-1.04 (s). MS(m/z) 858.0 [M+H]⁺.

Example 153

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(153)

The title compound (153) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 145 ofExample 145 utilizing 2-(prop-2-yn-1-yloxy)ethanol. ¹H NMR (400 MHz,cd₃od) δ 8.67 (d), 7.71 (dd), 7.62-7.52 (m), 7.17 (d), 7.07 (d),6.81-6.71 (m), 6.68-6.60 (m), 6.45-6.34 (m), 5.29-5.24 (m), 4.98 (q),4.84-4.70 (m), 4.54 (d), 3.86-3.80 (m), 3.80-3.66 (m), 3.36-3.31 (m),3.28-3.09 (m), 2.98 (d), 2.52-2.44 (m), 1.40 (q), 1.16-1.11 (m),1.10-1.05 (m). MS (m/z) 854.2 [M+H]⁺.

Example 154

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-4-methoxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(154)

The title compound (154) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 145 ofExample 145 utilizing 1-methoxy-2-methylbut-3-yn-2-ol. ¹H NMR (400 MHz,cd₃od) δ 8.67 (d), 7.71 (dd), 7.62-7.52 (m), 7.17 (d), 7.07 (d),6.81-6.71 (m), 6.64 (d), 6.45-6.34 (m), 5.26 (s), 4.98 (q), 4.84-4.70(m), 4.62 (s), 4.54 (d), 3.86-3.80 (m), 3.80-3.66 (m), 3.34 (s),3.28-3.09 (m), 2.98 (d), 2.48 (dd), 1.40 (q), 1.14 (m), 1.07 (m). MS(m/z) 869.1 [M+H]⁺.

Example 155

Synthesis of (E)-7-bromo-1-methyl-4-(prop-1-en-1-yl)-1H-indazol-3-amine(155A)

To 58B (7.4 g, 21.0 mmol) in dioxane (40 mL) and DMF (40 ml) was addedpotassium trifluoro(prop-1-en-1-yl)borate (3.7 g, 25.2 mmol), 2M K₂CO₃in water (21.0 ml), and Pd(PPh₃)₂Cl₂ (740.0 mg, 1.1 mmol). The reactionmixture was stirred for 2 hours at 100° C. The reaction was cooled,diluted with EtOAc and brine. The mixture was extracted 2× with EtOAc,the organic layer was dried over sodium sulfate, was concentrated andpurified by flash column chromatography to provide the title compound.MS (m/z) 266.3 [M+H]⁺.

Synthesis of(E)-N-(7-bromo-1-methyl-4-(prop-1-en-1-yl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(155B)

To 155A (3.7 g, 13.9 mmol) in DCM (100 mL) was addedN,N-diisopropylethylamine (9.7 ml, 55.6 mmol) then the reaction wascooled in an ice bath and methanesulfonyl chloride (3.2 ml, 41.7 mmol)was added. The reaction mixture was stirred for 30 minutes at 0° C. Thereaction was diluted with water and extracted 2× with DCM. The organiclayer was dried over sodium sulfate and concentrated. The mixture waspurified by flash column chromatography to provide the title compound.MS (m/z) 421.9 [M+H]⁺.

Synthesis ofN-(7-bromo-4-formyl-1-methyl-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(155C)

A round bottom is charged with 155B (2.7 g, 6.4 mmol) and DCM (100 mL).The mixture was cooled to −78° C. and ozone was bubbled into thereaction. Once the conversion was complete, DMS was added to quench thereaction under stirring for 30 minutes. To the stirring mixture asaturated sodium thiosulfate solution was added and the mixture wasallowed to warm to room temperature and stirred another 30 minutes. Thelayers were separated and the water layer was extracted again with DCM.The combined organic layers were dried over sodium sulfate andconcentrated. The residue was dissolved in DCM and followed by theaddition of hexane. The mixture was filtered to provide the titlecompound. MS (m/z) 410.0 [M+H]⁺.

Synthesis ofN-(7-bromo-4-(difluoromethyl)-1-methyl-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(155D)

A teflon flask was charged with 155C (650 mg, 1.6 mmol) and DCM (100mL). The mixture was cooled to 0° C. and Deoxo-Fluor (0.4 ml, 2.4 mmol)was added into the reaction and then the mixture was allowed to warm toroom temperature. The mixture is stirred for 8 hours and checked.Another equivalent of Deoxo-Fluor was added and the mixture was stirredovernight. The mixture is diluted with water and extracted 2× with DCM.The organic layers are dried over sodium sulfate and concentrated. Theresidue was dissolved in DCM followed by the addition of hexane. Themixture was filtered to provide the title compound. MS (m/z) 431.9[M+H]⁺.

Synthesis ofN-(7-bromo-4-(difluoromethyl)-1-methyl-1H-indazol-3-yl)methanesulfonamide(155E)

To 155D (5.9 g, 13.7 mmol), THF (50 ml) and MeOH (20 ml) was added asaturated solution of LiOH (10 ml) and water (10 ml). The mixture wasstirred for 10 minutes, then diluted with water and extracted 2× EtOAc.The organic layers were dried over sodium sulfate and concentrated. Theresidue was dissolved in DCM followed by the addition of hexane. Themixture was filtered to provide the title compound. MS (m/z) 354.6[M+H]⁺.

Synthesis ofN-(4-(difluoromethyl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(155F)

The title compound (155F) was prepared according to the method presentedfor the synthesis of compound 19C of Example 19 utilizing 155E. MS (m/z)402.3 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-(difluoromethyl)-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(155G)

To 14B (100 mg, 0.2 mmol) in dioxane (8 mL) and DMF (2 ml) was added 2NK₂CO₃ (0.2 ml), and Pd(PPh₃)₂Cl₂ (7.1 mg, 0.01 mmol). The reactionmixture was stirred at 110° C., then 155F (170 mg, 0.4 mml) dissolved indioxane (4 ml) and DMF (2 ml) was slower added into the reaction bysyringe. The reaction was cooled after 8 hours, diluted with EtOAc andbrine. The mixture was extracted 2× with EtOAc, the organic layer wasdried over sodium sulfate, was concentrated and purified by flash columnchromatography to provide the title compound as a mixture ofatropisomers. MS (m/z) 689.8 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-(difluoromethyl)-1-methyl-1H-indazol-3-yl)methanesulfonamide(155H)

The title compound (155H) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19F ofExample 19 utilizing 155G. MS (m/z) 590.1 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-(difluoromethyl)-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(155I)

The title compound (155I) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 155H and2-43bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (Chloroform-d) δ: 7.60 (dd), 7.53 (dd), 7.49-7.38 (m),7.30-7.19 (m), 7.14 (s), 6.83-6.78 (m), 6.70 (t), 6.69-6.62 (m), 6.34(d), 6.25-6.14 (m), 4.95 (q), 4.75-4.69 (m), 3.59-3.42 (m), 3.35 (s),3.01-2.88 (m), 2.56-2.36 (m), 1.72 (s), 1.46-1.37 (m), 1.19-1.09 (m). MS(m/z) 836.2 [M+H]⁺.

Example 156

Synthesis of ethyl1-(2-(tert-butoxy)-2-oxoethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate(156B)

To 156A (2 g, 10.3 mmol) in MeTHF (100 mL) and DMF (5 ml) was addedCs₂CO₃ (4.0 g, 12.3 mmol) and tert-butyl 2-bromoacetate (2.3 ml, 15.5mmol). The reaction mixture was stirred for 4 hours. Solids werefiltered, the eluent was concentrated and purified by flash columnchromatography to provide the title compound. MS (m/z) 309.6 [M+H]⁺.

Synthesis of tert-butyl2-(3-(1-hydroxycyclopropyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(156C)

To 156B (300 mg, 1.0 mmol) in MeTHF (20 mL) was added titanium (iv)isopropoxide (2.9 ml, 9.73 mmol). To the stirring mixture 3M EtMgBr (3.2ml) was slowly added. The reaction mixture was stirred for 1 hour. Thereaction was diluted with EtOAc and brine. The mixture was extracted 2×with EtOAc, the organic layer was dried over sodium sulfate, wasconcentrated and purified by flash column chromatography to provide thetitle compound. MS (m/z) 293.0 [M+H]⁺.

Synthesis of2-(3-(1-hydroxycyclopropyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (156D)

To 156C (20 mg, 0.07 mmol) in DCM (2 mL) was added TFA (0.5 ml). Thereaction mixture was stirred for 0.5 hours at RT. The reaction wasconcentrated and then diluted with 1 N HCl and extracted 2× with DCM.The water layer was lyophilized to provide the title compound. MS (m/z)237.1 [M+H]⁺.

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(1-hydroxycyclopropyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(156E)

The title compound (156E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 156D and 19F. ¹H NMR (Methanol-d₄) δ: 7.76-7.68(m), 7.53 (dd), 7.25-7.14 (m), 6.64 (tt), 6.39 (dd), 5.27 (dd), 4.64(d), 3.28-3.21 (m), 3.21-3.10 (m), 3.04 (s), 2.98 (dd), 2.67-2.55 (m),2.47-2.37 (m), 1.86-1.69 (m), 1.64 (s), 1.10-0.97 (m). MS (m/z) 792.3[M+H]⁺.

Example 157

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(157A)

(S)-tert-butyl(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (1.0 g,2.42 mmol),N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(19D, 1.12 g, 2.90 mmol), and PdCl₂[P(cy)₃]₂ (89.0 mg, 0.121 mmol) weresuspended in 1,4-dioxane (12 mL) and 1.0 M aqueous NaHCO₃ (4 mL). Thereaction mixture was degassed by bubbling argon for 5 minutes thensealed and heated at 150° C. for 15 minutes in a microwave reactor. Uponcooling, the reaction mixture was diluted with water and extracted withthree portions of EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, concentrated in vacuo, and purified by silica gelcolumn chromatography to give the title compound 157A. MS (m/z) 591.72[M+H]⁺.

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide(157B)

To (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(157A, 3.39 g, 5.73 mmol) in DCM (5 mL) was added trifluoroacetic acid(5 mL). The reaction mixture was stirred at room temperature for 2.5hours. Upon complete removal of the Boc protecting group,trifluoroacetic anhydride (2.02 mL, 14.31 mmol) was added. The reactionmixture was stirred at room temperature for 30 minutes. Upon completion,the reaction mixture was filtered through celite, concentrated in vacuo,taken in EtOAc, and carefully neutralized with 1M aqueous NaHCO₃ untilthe aqueous layer was at pH 10. The organic layer was collected and theaqueous layer extracted once more with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, concentrated in vacuo, andpurified by silica gel column chromatography to give the title compound157B. MS (m/z) 588.14 [M+H]⁺.

Synthesis of(S)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-(2-(3,5-difluorophenyl)-1-(2,2,2-trifluoroacetamido)ethyl)pyridine1-oxide (157C)

To a solution of(S)—N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide(157B, 8.0 g, 13.61 mmol) in DCM (70 mL) was added MCPBA (3.659 g, 16.33mmol) in 4 portions over a 15 minute period. The reaction mixture wasstirred at room temperature for 16 hours. Upon completion, the reactionwas quenched with 1M aqueous NaHSO₃ and saturated aqueous NaHCO₃. Theorganic layer was collected and the aqueous layer was extracted anadditional time with DCM. The combined organic layers were dried overNa₂SO₄, filtered, concentrated in vacuo, and purified by silica gelcolumn chromatography to give the title compound 157C. MS (m/z) 604.10[M+H]⁺.

Synthesis of(S)—N-(1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide(157D)

(S)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-(2-(3,5-difluorophenyl)-1-(2,2,2-trifluoroacetamido)ethyl)pyridine1-oxide (157C, 1.0 g, 1.66 mmol) was taken in POCl₃ (2.32 mL, 24.84mmol). The reaction mixture was heated at 115° C. for 2 hours. Uponcooling, the reaction was concentrated in vacuo, taken in DCM, andvigorously stirred with saturated aqueous NaHCO₃ for 1 hour. The organiclayer was collected, and the aqueous layer was extracted an additionaltime with DCM. The combined organic layers were dried over Na₂SO₄,filtered, concentrated in vacuo, and purified by silica gel columnchromatography to give the title compound 157D. MS (m/z) 622.13 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(157E)

To a solution of(S)—N-(1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide(157D, 870 mg, 1.40 mmol) in EtOH (16 mL) was added 2M aqueous LiOH (7.0mL, 13.98 mmol). The reaction was heated at 130° C. for 10 minutes. Uponcooling, the reaction mixture was acidified with 2N aqueous HCl until atpH 5. The reaction mixture was then concentrated in vacuo and taken inEtOAc. To the solution was added saturated aqueous NaHCO₃ until theaqueous layer was at pH 10. The organic layer was collected, and theaqueous layer was extracted an additional time with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated in vacuo,and used without further purification. MS (m/z) 526.06 [M+H]⁺.

Synthesis ofN—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(157F)

To a solution of crude(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(157E, 400 mg, 0.76 mmol) in DMA (6 mL) was added NEt₃ (0.32 mL, 2.28mmol),2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (160.6 mg, 0.61 mmol), then HATU (173.4 mg, 0.46 mmol). Thereaction mixture was stirred at room temperature for 15 minutes, thenadditional HATU (86.7 mg, 0.23 mmol) was added. The reaction mixture wasstirred at room temperature for an additional 15 minutes. Uponcompletion, the reaction mixture was concentrated in vacuo and purifiedby silica gel column chromatography to give the title compound 157F. MS(m/z) 790.12 [M+H]⁺.

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4,4-difluoro-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(157G)

N—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(157F, 20 mg, 0.025 mmol), 1,1-difluoro-2-methylbut-3-yn-2-ol (15.2 mg,0.126 mmol), PdCl₂(PPh₃)₂ (1.8 mg, 0.003 mmol), and CuI (0.5 mg, 0.003mmol) were taken in DMF (0.25 mL). To the reaction mixture was addeddiethylamine (26 μL, 0.253 mmol), and the reaction mixture was degassedby bubbling argon for 5 minutes then sealed and heated at 125° C. for 30minutes in a microwave reactor. Upon cooling, the reaction mixture wasfiltered and purified by reverse phase HPLC to give the title compound157G as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ8.88-8.78 (m), 7.74 (dd), 7.60 (dd), 7.24-7.13 (m), 7.10-7.05 (m), 6.77(t), 6.64 (t), 6.46-6.33 (m), 5.82 (t), 5.35-5.23 (m), 5.00 (q), 4.82(s), 4.79 (s), 4.76 (s), 3.34 (s), 3.26 (s), 3.23 (s), 3.20-3.10 (m),3.07-2.93 (m), 2.58-2.37 (m), 1.63 (s), 1.50-1.34 (m), 1.18-1.11 (m),1.10-1.01 (m). MS (m/z) 874.07 [M+H]⁺.

Example 158

Synthesis of (3b-S,4aR)-ethyl1-(2-methoxy-2-oxoethyl)-5-(methoxymethoxy)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158A)

To a solution of (3b-S,4aR)-ethyl5-(methoxymethoxy)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(140D) (3.3 g, 13.1 mmol) in DMF (12 ml) was added portionwise potassiumt-butoxide (1.61 g, 14.39 mmol) at 0° C. To the reaction was added2-methyltetrahydrofuran (12 ml) followed by a dropwise addition ofmethyl bromoacetate (1.36 ml, 14.4 mmol). After gradually warming toroom temperature and stirring for 1 h, the reaction was extracted withEtOAc and water. The organic layer was washed with water. The organicslayer was dried with Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was taken to next step without further purification. MS(m/z) 324.96 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl5-hydroxy-1-(2-methoxy-2-oxoethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158B)

To a solution of (3b-S,4aR)-ethyl1-(2-methoxy-2-oxoethyl)-5-(methoxymethoxy)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158A) (4.2 g) in acetic acid (15 ml) was added water (30 ml). Afterstirring at reflux for 2 h, the reaction was concentrated in vacuo. Theresulting mixture was diluted with dioxane (40 ml) and concentrated invacuo. The crude product was dissolved in dichloromethane (20 ml), driedwith Na₂SO₄, filtered, and concentrated in vacuo. The crude product wastaken to next step without further purification. MS (m/z) 281.02 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl1-(2-methoxy-2-oxoethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158C)

To a solution of 156B (3.63 g, 12.95 mmol) in DCM (30 mL) was added DessMartin periodinane (4.87 g, 12.95 mmol). The reaction was stirred atroom temperature overnight. The reaction mixture was filtered throughcelite, solid loaded onto silica and purified by silica gelchromatography to give the title compound. MS (m/z) 278.9 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl1-(2-methoxy-2-oxoethyl)-1,3b,4,4a-tetrahydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-3-carboxylate(158D)

To a solution of 158C (0.69 g, 2.61 mmol), 1,2-ethanedithiol (0.44 ml,5.22 mmol), acetic acid (0.75 ml, 13.06 mmol) in DCM (10 ml) was addedboron trifluoride diethyl etherate (0.81 ml, 6.53 mmol). The reactionwas stirred at room temperature for 2 days. The reaction mixture wasconcentrated, solid loaded onto silica and purified by silicachromatography to give the title compound 158D. MS (m/z) 354.9 [M+H]⁺.

Synthesis of (3b-S,4aR)-ethyl5,5-difluoro-1-(2-methoxy-2-oxoethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158E)

To suspension of N-iodosuccinimide, 98% (1.35 g, 6.0 mmol) in DCM (5 ml)was added dropwise 70% HF in pyridine (5 ml) at −78° C. After stirringfor 15 min 158D (0.85 g, 2.39 mmol) in DCM (5 ml) was added and thereaction was slowly warmed to −30° C. and stirred at that temperaturefor 1 h. The resulting solution was carefully poured onto ice containing1.0 N NaHCO₃. The product was extracted with ethyl acetate, washed withNaHSO₃, brine and water. The combined organic layers were dried withNa₂SO₄, filtered, and concentrated. The crude material was purified bysilica chromatography to give the title compound 158E. MS (m/z) 300.9[M+H]⁺.

Synthesis of sodium2-((3b-S,4aR)-3-(ethoxycarbonyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(158F)

To a solution of 158E (0.16 g, 532.87 μmol) in dioxane (3 ml) was addeddropwise 1M NaOH (0.55 ml). The reaction was stirred at room temperaturefor 0.5 h. An additional 0.500 mL of 1M NaOH was added and stirred foran additional 0.5 h. The reaction was concentrated, diluted with DMA (3mL) and concentrated until dryness. The crude product was taken to nextstep without further purification. MS (m/z) 286.9 [M+H]⁺.

Synthesis of (3bS,4aR)-ethyl1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(158G)

To a solution of 19F (305.45 mg, 532.1 μmol) and 158F (164 mg, 532.1μmol) in DMA (2 mL) was added HATU (212.31 mg, 558.7 μmol). The reactionwas stirred at room temperature for 0.5 h. The reaction was diluted with0.1 M NaCl (10 mL) and extracted with ethyl acetate (2×10 mL). Thecombined organic layers was washed with water (20 mL), dried withNa₂SO₄, filtered, and concentrated. The crude material was purified bysilica chromatography to give the title compound 158G as a mixture ofatropisomers. ¹H NMR (400 MHz, cd₃od) δ 8.77 (d), 8.75-8.68 (m), 8.43(dd), 7.70 (t), 7.57-7.48 (m), 7.22-7.15 (m), 7.06 (d), 6.81-6.72 (m),6.68-6.59 (m), 6.41 (dd), 5.30-5.19 (m), 4.99 (q), 4.82 (d), 4.73 (s),4.42-4.31 (m), 3.36 (s), 3.34-3.27 (m), 3.25 (s), 3.22 (s), 3.17 (dd),3.04-2.97 (m), 2.96 (s), 2.63-2.39 (m), 1.65 (s), 1.64 (s), 1.49-1.32(m), 1.14-1.07 (m), 1.07-0.99 (m). MS (m/z) 842.2 [M+H]⁺.

Example 159

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-cyano-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(159)

To a solution of 160 (11 mg, 12.2 μmol) in DMSO (0.2 ml) was addedcuprous cyanide (2.7 mg, 30.7 μmol). The reaction mixture sealed andheated to 180° C. for 0.5 h. The reaction was cooled rt, diluted withethyl acetate, and washed with water. The organic phase was then driedwith Na₂SO₄, filtered and concentrated. The crude material was purifiedby prep HPLC to provide the product 159 as a mixture of atropisomers. ¹HNMR (400 MHz, cd₃od) δ 8.87-8.78 (m), 7.73-7.66 (m), 7.58-7.48 (m), 7.18(s), 7.07 (d), 6.81-6.71 (m), 6.68-6.58 (m), 6.48-6.32 (m), 5.32-5.20(m), 5.03-4.91 (m), 4.80 (d), 3.34 (s), 3.25 (s), 3.24 (s), 3.15 (dd),3.06-2.93 (m), 2.63-2.47 (m), 1.64 (s), 1.45 (dd), 1.19-1.14 (m),1.11-1.06 (m). MS (m/z) 795.1 [M+H]⁺.

Example 160

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-iodo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(160)

To a solution of 148B (75 mg, 95.5 μmol) in trifluoroacetic acid (0.5ml) and water (0.2 mL was added sodium nitrite (1M in water, 0.3 mL)followed by stirring for 15 min at room temperature. The reactionmixture was then treated with potassium iodide (238 mg, 1.4 mmol),acetonitrile (0.8 mL) and stirred for an additional 1.5 h. The reactionwas basified with 1M NaHCO₃, quenched with 1M NaHSO₃, and extracted withethyl acetate (20 mL). The organic phase was then dried with Na₂SO₄,filtered and concentrated. The crude material was purified by prep HPLCto provide the product 160 as a mixture of atropisomers. ¹H NMR (400MHz, cd₃od) 67.75-7.63 (m), 7.58-7.48 (m), 7.18 (s), 7.12-7.02 (m),6.82-6.72 (m), 6.68-6.58 (m), 6.46-6.32 (m), 5.32-5.22 (m), 4.96 (t),4.76-4.56 (m), 3.34 (s), 3.30-3.22 (m), 3.26 (s), 3.25 (s), 3.20-3.06(m), 3.04-2.91 (m), 2.51-2.35 (m), 2.30-2.16 (m), 2.03 ( ), 1.65 (s),1.42-1.27 (m), 1.10-1.04 (m), 1.04-0.99 (m). MS (m/z) 896.0 [M+H]⁺.

Example 161

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(dimethylamino)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(161)

To a solution of 148B (10 mg, 12.7 μmol) in acetic acid (0.1 ml) andformaldehyde (35% in water, 6.7 μl, 63.6 μmol) was added sodiumcyanoborohydride (1.7 mg, 26.7 μmol) followed by stirring for 16 h atrt. The reaction mixture was diluted with ACN and purified by prep HPLCto provide the product 161 as a mixture of atropisomers. ¹H NMR (400MHz, cd₃od) δ 7.74-7.64 (m), 7.58-7.48 (m), 7.16 (q), 7.07 (d),6.82-6.72 (m), 6.68-6.56 (m), 6.45-6.30 (m), 5.28 (dd), 4.95 (t), 4.51(d), 4.47 (d), 3.33 (s), 3.26 (s), 3.25 (s), 3.27-3.18 (m), 3.09 (dd),2.98 (s), 2.92 (s), 2.92 (s), 2.49-2.40 (m), 2.40-2.28 (m), 1.65 (s),1.41-1.29 (m), 1.09-0.98 (m). MS (m/z) 813.2 [M+H]⁺.

Example 162

Synthesis of methyl((3bS,4aR)-1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-3-yl)carbamate(162)

To a solution of 148B (6 mg, 7.64 μmol) in DCM (0.1 ml) was addedpyridine (3.08 μl, 38.21 μmol) followed by methylchloroformate (0.7 mg,7.18 μmol) then stirred for 30 min at rt. The reaction was concentratedand the product was purified by prep HPLC to provide the product 162 asa mixture of atropisomers. ¹H NMR (400 MHz, cd₃od) δ 7.72-7.65 (m), 7.54(d), 7.51 (d), 7.17 (s), 7.06 (d), 6.81-6.73 (m), 6.67-6.59 (m),6.44-6.33 (m), 5.27 (dd), 4.96 (t), 4.59 (d), 4.54 (d), 3.76 (s), 3.75(s), 3.34 (s), 3.26 (s), 3.23 (s), 3.15-3.07 (m), 3.04-2.91 (m), 2.61(s), 2.37-2.22 (m), 1.64 (s), 1.37-1.25 (m), 1.06-0.99 (m), 0.99-0.93(m). MS (m/z) 843.2 [M+H]⁺.

Example 163

Synthesis of2-((3bS,4aR)-3-acetamido-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(163)

The title compound (163) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 162 ofExample 162 utilizing acetyl chloride. ¹H NMR (400 MHz, cd₃od) δ 7.69(t), 7.54 (d), 7.51 (d), 6.80-6.74 (m), 6.67-6.60 (m), 6.44-6.33 (m),5.27 (dd), 4.96 (t), 4.61 (s), 4.56 (d), 3.34 (s), 3.26 (s), 3.23 (s),3.16-3.07 (m), 3.02-2.92 (m), 2.68-2.56 (m), 2.34-2.23 (m), 2.12 (s),2.11 (s), 1.64 (s), 1.36-1.25 (m), 1.03-0.98 (m), 0.98-0.92 (m). MS(m/z) 827.1 [M+H]⁺.

Example 164

Synthesis of(3bS,4aR)-1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-N,N-dimethyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxamide(164)

To a solution of 148A (6 mg, 7.18 μmol) in DMA (100 μl) was added asolution of HATU (2.73 mg, 7.18 μmol) in DMA (50 μl) followed bydimethylamine (2M in THF, 50 μl, 0.1 mmol), then stirred for 16 h at rt.The reaction mixture was concentrated, filtered, and purified by reversephase HPLC to provide the product 164 as a mixture of atropisomers. ¹HNMR (400 MHz, cd₃od) δ 8.64 (d), 8.59 (d), 7.76-7.65 (m), 7.54 (d), 7.51(d), 7.16 (s), 7.08 (d), 6.80-6.72 (m), 6.66-6.60 (m), 6.44 (d),6.42-6.34 (m), 5.28 (dd), 4.98 (t), 4.78 (s), 4.73 (d), 3.34 (s), 3.33(s), 3.28 (s), 3.25 (s), 3.23 (s), 3.15-3.07 (m), 3.09 (s), 3.07 (s),3.03-2.92 (m), 2.57-2.38 (m), 1.66-1.61 (m), 1.43-1.26 (m), 1.13-1.07(m), 1.03 (dt). MS (m/z) 841.1 [M+H]⁺.

Example 165

Synthesis of(3bS,4aR)-1-(2-(((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-5,5-difluoro-N-methyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxamide(165)

The title compound (165) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 164 ofExample 164 utilizing methylamine. ¹H NMR (400 MHz, cd₃od) δ 8.65-8.60(m), 7.18-7.07 (m), 6.79-6.61 (m), 7.73-7.65 (m), 7.54 (d), 7.51 (d),7.17 (s), 7.08 (d), 6.81-6.71 (m), 6.65-6.57 (m), 6.45 (d), 6.42-6.34(m), 5.29 (dd), 4.97 (t), 4.78 (s), 4.72 (d), 3.34 (s), 3.25 (s), 3.21(s), 3.24-3.11 (m), 3.02-2.93 (m), 2.88 (s), 2.87 (s), 2.69-2.52 (m),2.51-2.36 (m), 1.64 (s), 1.45-1.24 (m), 1.10-1.02 (m), 1.02-0.95 (m). MS(m/z) 827.2 [M+H]⁺.

Example 166

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3,4-dihydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(166)

The title compound (166) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 142 ofExample 142 utilizing 2-methylbut-3-yne-1,2-diol. ¹H NMR (400 MHz,cd₃od) 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d), 7.70 (dd), 7.62-7.52(m), 7.17 (s), 7.06 (d), 6.88-6.66 (m), 6.65-6.52 (m), 6.44-6.32 (m),5.00-4.93 (m), 4.78-4.64 (m), 3.67 (s), 3.24 (d), 3.02-2.92 (m),2.49-2.42 (m), 1.59 (s), 1.40-1.34 (m), 1.12-1.07 (m), 1.05-0.98 (s). MS(m/z) 837.9 [M+H]⁺.

Example 167

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-cyclopropyl-4-(2-hydroxyethyl)-5-methyl-1H-pyrazol-1-yl)acetamide(167)

The title compound (167) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and2-(3-cyclopropyl-4-(2-hydroxyethyl)-5-methyl-1H-pyrazol-1-yl)acetic acid(prepared as described in US2012045761). ¹H NMR (400 MHz, Methanol-d₄) δ7.71 (dd), 7.53 (dd), 7.27-7.15 (m), 7.12 (d), 6.80-6.70 (m), 6.69-6.58(m), 6.55 (d), 6.44-6.29 (m), 5.33-5.22 (m), 5.03-4.93 (m), 4.73-4.52(m), 3.69-3.53 (m), 3.32 (s), 3.27-3.21 (m), 3.17-3.08 (m), 3.05 (s),2.99-2.85 (m), 2.76-2.60 (m), 2.11 (s), 2.01 (s), 1.88-1.78 (m), 1.64(s), 0.93-0.86 (m), 0.79-0.70 (m). MS (m/z) 780.8 [M+H]⁺.

Example 168

Synthesis ofN—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(168A)

The title compound (168A) was prepared according to the method presentedfor the synthesis of compound 157F of Example 157 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. MS (m/z) 772.03 [M+H]⁺.

Synthesis ofN—((S)-1-(6-(1-(tert-butyl)-1H-pyrazol-4-yl)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(168B)

N—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(168A, 20 mg, 0.026 mmol), 1-t-Butylpyrazole-4-boronic acid, pinacolester (7.77 mg, 0.031 mmol), Pd(PPh₃)₄ (1.50 mg, 0.001 mmol), and K₂CO₃(10.7 mg, 0.078 mmol) were suspended in 1,4-dioxane (0.2 mL). To thesuspension was added water (0.05 mL). The resulting reaction mixture wasdegassed by bubbling argon for 60 seconds then sealed and heatedthermally at 110° C. for 3.5 hours. Upon completion, the reactionmixture was filtered, concentrated in vacuo, taken in DMF, and purifiedby reverse phase HPLC to give the title compound 168B as a mixture ofatropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.51 (s), 8.50 (s), 8.25(s), 8.22 (d), 7.70 (t), 7.68-7.60 (m), 7.17 (s), 7.08 (s), 7.06 (s),6.87-6.51 (m), 6.46-6.33 (m), 5.34-5.24 (m), 4.98 (dd), 4.81 (s), 4.79(s), 4.77 (s), 3.38 (s), 3.26 (s), 3.24 (s), 3.22-3.17 (m), 3.04 (s),2.98 (dd), 2.53-2.36 (m), 1.70 (s), 1.46-1.27 (m), 1.08 (m), 1.00 (m).MS (m/z) 860.21 [M+H]⁺.

Example 169

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4,4-difluoro-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(169)

The title compound (169) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 142 ofExample 142 utilizing 1,1-difluoro-2-methylbut-3-yn-2-ol. ¹H NMR (400MHz, cd₃od) δ 8.73 (t), 7.77-7.68 (d), 7.64-7.59 (m), 7.22-7.13 (m),7.07 (dd), 6.87-6.51 (m), 6.46-6.34 (m), 5.82 (t), 5.37-5.21 (m),5.04-4.93 (m), 4.78-4.63 (m), 3.24 (d), 3.05-2.93 (m), 2.45 (m), 1.63(s), 1.47-1.32 (m), 1.08 (s), 1.01 (s). MS (m/z) 857.1 [M+H]⁺.

Example 170

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4-fluoro-3-(fluoromethyl)-3-hydroxybut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(170)

N—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(168A, 20 mg, 0.025 mmol), 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol (15.5mg, 0.129 mmol), PdCl₂(PPh₃)₂ (1.8 mg, 0.003 mmol), and CuI (0.5 mg,0.003 mmol) were suspended in DMF (0.25 mL). To the reaction mixture wasadded diethylamine (27 μL, 0.259 mmol), and the reaction mixture wasdegassed by bubbling argon for 5 minutes then sealed and heated at 125°C. for 30 minutes in a microwave reactor. Upon cooling, the reactionmixture was filtered and purified by reverse phase HPLC. Fractionscontaining the product were pooled and lyophilized to give the titlecompound 170 as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄)δ 8.72 (t), 7.74 (dd), 7.61 (dd), 7.22-7.14 (m), 7.09 (s), 7.07 (s),6.87-6.53 (m), 6.46-6.35 (m), 5.35-5.26 (m), 4.99 (q), 4.76 (s), 4.72(s), 4.70 (s), 4.66 (d), 4.54 (d), 3.33 (s), 3.26 (s), 3.23 (s),3.18-3.09 (m), 3.05-2.91 (m), 2.54-2.37 (m), 1.45-1.33 (m), 1.09 (s),1.02 (s). MS (m/z) 856.09 [M+H]⁺.

Example 171

Synthesis of(4-chloro-1-methyl-3-(trifluoromethylsulfonamido)-1H-indazol-7-yl)boronicacid (171A)

4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(19C) (0.20 g, 0.65 mmol) was dissolved in dichloromethane (10 mL) andtriethylamine (0.36 mL, 2.6 mmol). The mixture was cooled to 0° C. andtriflic anhydride (0.55 g, 1.95 mmol) was added dropwise. After stirringfor 30 minutes the reaction was quenched with water (10 mL) andextracted with dichloromethane (3×20 mL). The combined extracts werewashed with brine and evaporated under vacuum. The residue was dissolvedin ethanol (10 mL) and cooled to 0° C. 50% aqueous KOH solution (0.2 mL)was added dropwise and stirring was continued for 30 minutes. Themixture was acidified with 1N aqueous HCl. The formed precipitate wasfiltered and dried to give the title compound. MS (m/z) 358.0 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(trifluoromethylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(171B)

(4-chloro-1-methyl-3-(trifluoromethylsulfonamido)-1H-indazol-7-yl)boronicacid (171A, 26 mg, 0.073 mmol), (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(14B, 36 mg, 0.073 mmol), and PdCl₂(PPh₃)₂ (5.1 mg, 0.007 mmol) weresuspended in 1,4-dioxane (1 mL) and 1.0 M aqueous NaHCO₃ (1 mL). Thereaction mixture was heated at 150° C. for 15 minutes in a microwavereactor. After cooling, the reaction mixture was diluted with EtOAc (50mL), washed with water and brine, concentrated in vacuo, and purified bysilica gel column chromatography, eluting with 20-100% EtOAc in hexanesto give the title compound. MS (m/z) 728.3 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)-1,1,1-trifluoromethanesulfonamide(171C)

To a solution of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(trifluoromethylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(171B, 43 mg, 0.059 mmol) in DCM (1 mL) was added trifluoroacetic acid(1 mL). The reaction mixture was stirred at room temperature for 3 hoursand then concentrated in vacuo and azeotroped once with toluene (20 mL)to give the title compound. MS (m/z) 628.2 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(trifluoromethylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(171D)

To a solution of crude(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-((2-hydroxyethyl)(methyl)amino)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(171C, 44 mg, 0.059 mmol) in DMF (1 mL) was added2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (15.6 mg, 0.059 mmol), and HATU (27 mg, 0.071 mmol) followed bydiisopropylethylamine (31 μL, 0.177 mmol). After stirring for two hoursat ambient temperature, the reaction mixture was filtered and purifiedby reverse phase HPLC to provide the title compound as a mixture ofatropisomers. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (d), 8.95 (d), 7.87 (d),7.83 (d), 7.51 (d), 7.26 (d), 7.19 (s), 7.12-6.74 (m), 6.62-6.56 (m),6.49-6.35 (m), 4.95 (q), 4.79-4.54 (m), 3.26 (s), 3.06 (s), 3.31-2.92(m), 2.58-2.38 (m), 1.52 (s), 1.42-1.30 (m), 0.95-0.78 (m). MS (m/z)874.2 [M+H]⁺.

Example 172

Synthesis ofN—((S)-1-(5-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-[2,2′-bipyridin]-6-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(172)

To the reaction vial containing 157F (20 mg, 0.025 mmol) in dioxane(0.25 mL) was added 2-(tributylstannyl)pyridine (0.01 mL, 0.027 mmol),Pd(dppf)Cl₂.DCM (1.2 mg, 0.001 mmol), and KF (4 mg, 0.75 mmol). Thereaction mixture was flushed with argon gas for 5 min then sealed andheated in a microwave reactor to 135° C. for 30 min. Upon cooling, thereaction mixture was filtered and purified by reverse phase HPLC toprovide the title compound 172 as a mixture of atropisomers. ¹H NMR (400MHz, cd₃od) δ 9.90-9.8 (m), 8.80-8.76 (m), 8.74-8.70 (m), 8.52-8.45 (m),7.98-7.88 (m, 1H), 7.30-7.04 (m), 6.82-6.71 (m), 6.51-6.34 (m),5.45-5.35 (m), 5.14-5.05 (m), 4.98-4.86 (m), 3.35 (s), 3.21-3.00 (m),2.60-2.38 (m), 1.42-1.22 (m), 1.19-1.09 (m), 1.06-1.00 (m). MS (m/z)833.2 [M+H]⁺.

Example 173

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(173)

N—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(157F, 20 mg, 0.025 mmol), 1-methylpyrazole-4-boronic acid (3.8 mg,0.030 mmol), Pd(PPh₃)₄ (1.5 mg, 0.001 mmol), and K₂CO₃ (10.5 mg, 0.076mmol) were suspended in 1,4-dioxane (0.2 mL). To the suspension wasadded water (0.05 mL). The resulting reaction mixture was degassed bybubbling argon for 60 seconds then sealed and heated thermally at 110°C. for 2 hours. Upon completion, the reaction mixture was filtered,concentrated in vacuo, taken in DMF, and purified by reverse phase HPLCto give the title compound 173 as a mixture of atropisomers. ¹H NMR (400MHz, Methanol-d₄) δ 8.39 (s), 8.35 (s), 8.23 (s), 8.20 (s), 7.71-7.60(m), 7.15 (s), 7.06 (d), 6.76 (tt), 6.63 (tt), 6.49-6.41 (m), 6.41-6.34(m), 5.24 (dd), 4.99 (dd), 4.03 (s), 4.02 (s), 3.46-3.41 (m), 3.39 (s),3.26 (s), 3.24 (s), 3.23-3.17 (m), 3.07-2.95 (m), 2.59-2.38 (m),1.49-1.34 (m), 1.17-1.11 (m), 1.09-1.03 (m). MS (m/z) 836.16 [M+H]⁺.

Example 174

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(174)

The title compound (174) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 173 ofExample 173 utilizing 1-isopropylpyrazole-4-boronic acid, pinacol ester.¹H NMR (400 MHz, Methanol-d₄) δ 8.46 (s), 8.44 (s), 8.24 (s), 8.22 (s),7.72-7.60 (m), 7.16 (s), 7.06 (d), 6.76 (tt), 6.68-6.57 (m), 6.49-6.42(m), 6.41-6.33 (m), 5.26 (dd), 4.99 (dd), 4.86 (s), 4.70-4.58 (m),3.47-3.40 (m), 3.39 (s), 3.37-3.34 (m), 3.26 (s), 3.24 (s), 3.23-3.16(m), 3.09-2.93 (m), 2.59-2.37 (m), 1.61 (d), 1.49-1.34 (m), 1.17-1.11(m), 1.09-1.02 (m). MS (m/z) 864.20 [M+H]⁺.

Example 175

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(175)

The title compound (175) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 173 ofExample 173 utilizing 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.¹H NMR (400 MHz, Methanol-d₄) δ 7.87-7.78 (m), 7.59 (d), 7.31 (d), 7.20(d), 7.11 (d), 6.90 (d), 6.88 (d), 6.79 (tt), 6.63 (tt), 6.55-6.51 (m),6.47-6.37 (m), 5.40 (dd), 5.07 (dd), 4.78 (s), 4.77 (s), 4.43 (s), 4.34(s), 3.39 (s), 3.25 (s), 3.24-3.21 (m), 3.15-3.12 (m), 3.11-3.02 (m),2.59-2.35 (m), 1.47-1.33 (m), 1.15-1.08 (m), 1.06-0.98 (m). MS (m/z)836.15 [M+H]⁺.

Example 176

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(pyrimidin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(176)

The title compound (176) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 172 ofExample 172 utilizing 2-(tributylstannyl)pyrimidine. ¹H NMR (400 MHz,cd₃od) δ 9.90-9.86 (m), 9.84-9.80 (m), 8.80-8.75 (m, 1H), 8.74 (d), 8.47(d), 7.92 (t), 7.25-7.12 (m), 6.80-6.50 (m), 6.45-6.40 (m), 5.45-5.38(m), 5.15-5.05 (m), 4.90-4.81 (m), 3.37 (s), 3.18-3.04 (m), 2.50-2.39(m), 1.44-1.25 (m), 1.15-1.09 (m), 1.08-0.97 (m). MS (m/z) 835.1 [M+H]⁺.

Example 177

Synthesis of (S)-tert-butyl(1-(5-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(177A)

Compound 183A (0.500 g, 0.82 mmol) was added to a stirred suspension oft-BuONO (0.15 mL, 1.24 mmol) and CuBr₂ (0.276 g, 1.24 mmol) inacetonitrile with ice bath, the suspension was allowed to warm up toroom temperature and stirred overnight. Aqueous ammonium chloride wasadded. The mixture was extracted with EtOAc. The organic layer was driedwith MgSO₄, concentrated and purified by silica gel column to afford thetitle compound as mixture of atropisomers (177A). MS (m/z) 670 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-phenylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(177B)

Compound 177A (31.3 mg, 0.047 mmol), phenylbronic acid (6.3 mg, 0.051mmol), K₂CO₃ (39 mg, 0.28 mmol) and Pd(dppf)Cl₂ (14 mg, 0.019 mmol) weremixed together. Toluene (1 mL), iPrOH (0.5 mL) and water (1 mL) wereadded. The vial was capped tight, stirred at 60° C. for 30 minutes. Thereaction mixture was diluted with EtOAc, washed with brine, dried withMgSO₄ and concentrated. The crude was purified by silica gel column toafford the title compound as mixture of atropisomers (177B). MS (m/z)668 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-phenylpyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(177C)

Compound 177B (21.7 mg, 0.032 mmol) was dissolved in DCM (1 mL). TFA(0.5 mL) was added. The resultant solution was stirred at ambienttemperature for 2 hours. The reaction was concentrated to afford titlecompound as mixture of atropisomers (177C). MS (m/z) 568 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-phenylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(177D)

Compound 177C (18.4 mg, 0.032 mmol) and2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (8.6 mg, 0.032 mmol) were dissolved in DMF (1 mL). TEA (23 uL,0.162 mmol) and HATU (18.5 mg, 0.049 mmol) were added. Upon completion,a few drops of 1M HCl were added. The reaction was purified by HPLC toafford the title compound as mixture of atropisomers (177D). ¹H NMR (400MHz, Acetonitrile-d3) δ 9.04 (dd), 7.99 (dd), 7.82-7.73 (m), 7.69 (d),7.59-7.43 (m), 7.34 (d), 7.29-7.18 (m), 7.15 (d), 6.90 (d), 6.85-6.73(m), 6.69-6.58 (m), 6.49-6.36 (m), 5.30 (q), 4.96 (q), 4.69 (d), 3.33(s), 3.28 (s), 3.27 (s), 3.20-2.91 (m), 2.58-2.40 (m), 1.40 (q),1.09-0.97 (m). MS (m/z) 814 [M+H]⁺.

Example 178

Synthesis ofN—((S)-1-(6-(2-(tert-butyl)thiazol-5-yl)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(178)

N—((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(157F, 20 mg, 0.025 mmol), 2-(tert-butyl)-5-(tributylstannyl)thiazole(12.03 mg, 0.028 mmol), Pd(dppf)Cl₂ (1.1 mg, 0.001 mmol), and KF (4.4mg, 0.076 mmol) were suspended in 1,4-dioxane (0.25 mL). The resultingreaction mixture was degassed by bubbling argon for 60 seconds thensealed and heated at 130° C. for 30 minutes in a microwave reactor. Uponcooling, the reaction mixture was filtered, concentrated in vacuo, takenin DMF, and purified by reverse phase HPLC to give the title compound178 as a mixture of atropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.40(s), 7.91 (dd), 7.76 (d), 7.74 (d), 7.20-7.13 (m), 7.08 (d), 6.77 (tt),6.65 (tt), 6.55-6.47 (m), 6.45-6.38 (m), 5.20 (dd), 5.02 (dd), 4.80 (s),3.41 (s), 3.26 (s), 3.25 (s), 3.09-2.98 (m), 2.95 (s), 2.60-2.39 (m),1.71 (s), 1.70 (s), 1.69 (s), 1.48-1.34 (m), 1.17-1.11 (m), 1.09-1.03(m). MS (m/z) 897.04 [M+H]⁺.

Example 179

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(179)

The title compound (179) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 178 ofExample 178 utilizing 1-methyl-4-(tributylstannyl)-1H-imidazole. ¹H NMR(400 MHz, Methanol-d₄) δ 8.89 (s), 8.84 (s), 8.29 (s), 8.25 (s),7.94-7.82 (m), 7.19 (s), 7.07 (d), 6.78 (tt), 6.64 (tt), 6.48-6.41 (m),6.37 (dd), 5.35 (dd), 5.05 (dd), 4.81 (s), 4.77 (s), 4.05 (s), 4.04 (s),3.36 (s), 3.27 (s), 3.25 (s), 3.23-3.18 (m), 3.12-2.98 (m), 2.59-2.41(m), 1.48-1.37 (m), 1.33-1.26 (m), 1.16-1.10 (m), 1.09-1.03 (m). MS(m/z) 836.15 [M+H]⁺.

Example 180

Synthesis of tert-butyl((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfinamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(180A)

(S)-tert-butyl(1-(3-(3-amino-4-chloro-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(55A, 61 mg, 0.102 mmol) was dissolved in dichloromethane (2 mL) anddiisopropylethylamine (0.071 mL, 0.409 mmol). The mixture was cooled to0° C. and methanesulfinyl chloride (30.3 mg, 0.307 mmol) was addeddropwise. After stirring at ambient temperature overnight the reactionmixture was diluted with ethyl acetate (50 mL), washed with water andbrine and evaporated under vacuum. Purification on silica gel gave thetitle compound. MS (m/z) 658.3 [M+H]⁺.

Synthesis ofN-(7-(2-((S)-1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfinamide(180B)

To a solution of tert-butyl((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfinamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(180A, 50 mg, 0.076 mmol) in DCM (1 mL) was added trifluoroacetic acid(1 mL). The reaction mixture was stirred at room temperature for 3 hoursand then concentrated in vacuo and azeotroped once with toluene (20 mL)to give the title compound. MS (m/z) 558.2 [M+H]⁺.

Synthesis ofN-((1S)-1-(3-(4-chloro-1-methyl-3-(methylsulfinamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(180C)

To a solution of crudeN-(7-(2-((S)-1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfinamide(180B, 52 mg, 0.076 mmol) in DMF (1 mL) was added2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (20 mg, 0.076 mmol), and HATU (34.7 mg, 0.091 mmol) followed bydiisopropylethylamine (66 μL, 0.38 mmol). After stirring for two hoursat ambient temperature, the reaction mixture was filtered and purifiedby reverse phase HPLC to provide the title compound as a mixture ofdiastereomers and atropisomers. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99-8.60(m), 7.85-7.70 (m), 7.55 (d), 7.05-6.70 (m), 6.56-6.28 (m), 4.93-4.49(m), 3.30-2.59 (m), 2.96 (s), 2.65 (s), 2.48-2.30 (m), 1.72-1.66 (m),1.42-1.30 (m), 0.95-0.78 (m). MS (m/z) 804.2 [M+H]⁺.

Example 181

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(2-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(181A)

The title compound as mixture of atropisomers (181A) was preparedaccording to the method presented for the synthesis of compound 177B ofExample 177 utilizing compound 177A and 2-chlorophenylbronic acid. MS(m/z) 702 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(2-chlorophenyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(181A)

The title compound as mixture of atropisomers (181B) was preparedaccording to the method presented for the synthesis of compound 177C ofExample 177 utilizing compound 181A. MS (m/z) 602 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(2-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(181C)

The title compound as mixture of atropisomers (181C) was preparedaccording to the method presented for the synthesis of compound 177D ofExample 177 utilizing compound 181B and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, DMSO-d6) δ 9.82 (s), 9.75 (s), 9.07 (d), 8.94(d), 8.87 (dd), 7.97 (d), 7.90 (d), 7.69-7.39 (m), 7.23-6.74 (m), 6.54(d), 6.44 (d), 5.03 (q), 4.90-4.53 (m), 3.32 (s), 3.23-2.89 (m),2.60-2.37 (m), 1.47-1.30 (m), 0.83 (s). MS (m/z) 848 [M+H]⁺.

Example 182

Synthesis of 2-(5-bromo-6-methylpyridin-3-yl)isoindoline-1,3-dione(182A)

A mixture of phthalic anhydride (3.7 g, 25 mmol),5-bromo-6-methylpyridin-3-amine (3.9 g, 20.85 mmol) and sodium acetate(1.5 g, 25 mmol) in glacial acetic acid (44 ml) was refluxed forovernight. After cooling down to room temperature, the precipitate wascollected by vacuum filtration and washed with water. Then it was driedunder high vacuum to afford the title compound 182A. MS (m/z) 318.91[M+H]⁺.

Synthesis of 3-bromo-5-(1,3-dioxoisoindolin-2-yl)picolinaldehyde (182B)

To a microwave tube was charged with compound 182A (1.5 g, 4.73 mmol)and selenium dioxide (682 mg, 6.15 mmol). To it was added 14 mL of1,2-dimethoxyethane and the microwave tube was sealed. The reactionmixture was heated in a 130° C. heating bath for 20 hours. The reactionmixture was cooled down and the solids filtered off. The filtrate wasconcentrated to afford the title compound 182B. ¹H NMR (400 MHz, DMSO) δ10.04 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.07-7.84(m, 4H).

Synthesis of(S,Z)—N-((3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(182C)

Copper(II) sulfate (anhydrous, 5.8 g, 36.2 mmol) was added to a solutionof 3-bromo-5-(1,3-dioxoisoindolin-2-yl)picolinaldehyde (182B, 6 g, 18mmol) and (S)-2-methylpropane-2-sulfinamide (2.2 g, 18 mmol) in CH₂Cl₂(60 mL). The reaction mixture was stirred at ambient temperature for 2hours and then filtered and washed with CH₂Cl₂. The filtrate wasconcentrated and the residue was purified by silica gel chromatographyeluting with EtOAc and methylene chloride to yield the title compound182C. MS (m/z) 433.87 [M+H]⁺.

Synthesis of(S)—N—((S)-1-(3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(182D)

To a solution of compound (182C, 3.7 g, 8.5 mmol) and Cu(OTf)₂ (154 mg,0.4 mmol) in methylene chloride (30 ml) at 0° C. was added(3,5-difluorobenzyl)zinc bromide (0.5 M in THF, 25.5 ml, 12.8 mmol)dropwise. The reaction stirred at room temperature for one hour.Ammonium chloride (aq, 100 ml) was added to the reaction and the mixturewas extracted with methylene chloride (2×100 ml). The organic layer wasdried over Na₂SO₄ filtered and concentrated. The reaction mixture waspurified by silica gel chromatography then by reverse phase HPLC toafford the title compound 182D. MS (m/z) 563.83 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(182E)

Compound 182D (2.6 g, 4.6 mmol) was dissolved in 40 mL of methanol andcooled to 0° C. To it was added 4N HCl/1,4-dioxane (4.6 ml). Thereaction mixture was allowed to stir at room temperature for 10 minutesand concentrated to afford product(S)-2-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-3-yl)isoindoline-1,3-dionehydrochloride. To the mixture of the above HCl salt (˜4.6 mmol) andDi-tert-Butyl dicarbonate (1 g, 4.6 mmol) in 50 mL of CH₂Cl₂ was addedtriethylamine (1.28 mL, 9.2 mmol) at 0° C. The reaction mixture wasstirred for overnight and concentrated in vacuo. The residue waspartitioned between EtOAc and water. The organic layer was washed withbrine, dried over MgSO4, filtered and concentrated. Then it was purifiedon silica gel chromatography to yield the title compound 182E. MS (m/z)559.71 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(5-amino-3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(182F)

To a mixture of compound 182E (1.5 g, 2.7 mmol) in 27 ml of ethanol, 0.9ml of hydrazine monohydrate was added and stirred at room temperaturefor 2 hours. More ethanol was added to the reaction mixture. Theprecipitate was filtered off and the filtrate was concentrated. Theresidue was diluted with ethyl acetate, and washed with water and thenwith a saturated sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give the title compound 182F. MS (m/z) 427.83 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(5-amino-3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(182G)

A solution of compound 182F (960 mg, 2.24 mmol) in 20 mL of acetonitrilewas cooled to 0° C. and treated with N-Bromosuccinimide (399 mg, 2.24mmol) as a solution in 20 mL of acetonitrile. The reaction mixture waspartitioned with EtOAc and saturated aqueous NaHCO₃. The organic layerwas separated and washed with brine, then dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography to afford the title compound 182G. MS (m/z): 507.52[M+H]⁺.

Synthesis of (S)-tert-butyl(1-(5-amino-3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(182H)

The title compound (182H) was prepared according to the method presentedfor the synthesis of compound 4F of Example 4 utilizing compound 182G.MS (m/z) 511.87 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(methylamino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(182I)

Compound 182H (200 mg, 0.39 mmol) was dissolved in 2 mL of acetonitrile,to it was added formaldehyde (0.1 mL, 37% in H₂O) and acetic acid (0.2mL, 4 mmol) followed by slow addition of sodium cyanoborohydridesolution (1.2 mL, 1M in THF). The reaction mixture was allowed to stirat room temperature for 3 hours and quenched by adding aqueous sodiumbicarbonate. It was extracted with ethyl acetate. The organic layer waswashed with water, dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by RP-HPLC to afford the titlecompound 182I. MS (m/z): 525.99 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(methylamino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(182J)

The title compound (182J) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing compound 182I and compound 19D. MS (m/z) 703.35[M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(methylamino)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(182K)

The title compound (182K) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 105C ofExample 105 utilizing compound 182J. MS (m/z) 603.17 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(methylamino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(182L)

The title compound (182L) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 37E ofExample 37 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 182K. ¹H NMR (400 MHz, Methanol-d₄) δ 7.00 (d), 6.82(d), 6.76 (tt), 6.70 (t), 6.43-6.30 (m), 6.24 (d), 4.78-4.56 (m), 3.39(s), 3.22 (s), 3.16-2.99 (m), 2.98-2.88 (m), 2.84 (s), 2.52-2.31 (m),1.66 (d), 1.49-1.21 (m), 1.12-0.86 (m). MS (m/z) 849.90 [M+H]⁺.

Example 183

Synthesis of (S)-tert-butyl(1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(183A)

The title compound (183A) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 19E ofExample 19 utilizing compound 182F and compound 19D. MS (m/z) 606.88[M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(dimethylamino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(183B)

The title compound (183B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 182I ofExample 182 utilizing compound 183A. MS (m/z) 635.48 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(dimethylamino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(183C)

The title compound (183C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 182G ofExample 182 utilizing compound 183B. MS (m/z) 714.81 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(dimethylamino)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(183D)

The title compound (183D) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 4F ofExample 4 utilizing compound 183C. MS (m/z) 717.62 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(dimethylamino)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(183E)

The title compound (183E) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 105C ofExample 105 utilizing compound 183D. MS (m/z) 617.09 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-(dimethylamino)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(183F)

The title compound (183F) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 37E ofExample 37 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and compound 183E. ¹H NMR (400 MHz, Methanol-d₄) δ 7.26-7.10 (m),7.03 (d), 6.76 (t), 6.69 (t), 6.60 (t), 6.52-6.33 (m), 6.32 (d),4.85-4.78 (m), 4.78-4.60 (m), 3.37 (s), 3.23 (d), 3.10 (dd), 2.99 (d),2.98-2.74 (m), 2.45 (ddd), 1.66 (s), 1.48-1.30 (m), 1.17-0.92 (m)). MS(m/z): 863.19 [M+H]⁺.

Example 184

Synthesis of tert-butyl(4-(5-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-2-yl)-2-hydroxy-2-methylbut-3-yn-1-yl)carbamate(184)

The title compound (184) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 145 ofExample 145 utilizing tert-butyl(2-hydroxy-2-methylbut-3-yn-1-yl)carbamate. MS (m/z) 953.9 [M+H]⁺. HPLCretention time 7.54 min and 7.69 min (2-98% acetonitrile:water with 0.1%trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18column).

Example 185

Synthesis of (S)-tert-butyl(1-(5-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-[3,3′-bipyridin]-6-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(185A)

The title compound as mixture of atropisomers (185A) was preparedaccording to the method presented for the synthesis of compound 177B ofExample 177 utilizing compound 177A and 3-pyridinebronic acid. MS (m/z)669 [M+H]⁺.

Synthesis of(S)—N-(7-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-[3,3′-bipyridin]-5-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(185B)

The title compound as mixture of atropisomers (185B) was preparedaccording to the method presented for the synthesis of compound 177C ofExample 177 utilizing compound 185A. MS (m/z) 569 [M+H]⁺.

Synthesis ofN—((S)-1-(5-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-[3,3′-bipyridin]-6-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(185C)

The title compound as mixture of atropisomers (185C) was preparedaccording to the method presented for the synthesis of compound 177D ofExample 177 utilizing compound 185B. ¹H NMR (400 MHz, Acetonitrile-d3) δ9.07 (t), 8.96 (dd), 8.66 (dd), 8.15-8.06 (m), 8.03 (dd), 7.56-7.44 (m),7.35 (d), 7.28 (d), 7.22 (d), 7.16 (dd), 6.93-6.87 (m), 6.86-6.72 (m),6.69-6.57 (m), 6.48-6.34 (m), 5.37-5.29 (q), 4.98 (q), 4.78-4.59 (m),3.36-2.91 (m), 2.49 (dtd), 1.41 (p), 1.05 (t). MS (m/z) 815 [M+H]⁺.

Example 186

Synthesis of (S)-tert-butyl (1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-cyanopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(186A)

To a suspension of 177A (140 mg, 0.21 mmol) in anhydrous/degassed DMF(1.5 ml) was treated with Zn(CN)₂ (14.7 mg, 0.125 mmol), andtetrakis(triphenylphosphine)palladium(0) (24.1 mg, 0.021 mmol). Themixture was heated at 90° C. for 16 hours under a nitrogen atmosphere.The reaction mixture was allowed to cool to ambient temperature andpoured into EtOAc (50 ml). The organic layer was washed with brine,dried (MgSO₄), and concentrated under reduced pressure. The residue waspurified on flash column to provide the title compound as a mixture ofatropisomers. MS (m/z) 617 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-cyanopyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamidehydrochloride (186B)

The title compound (186B) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 21E ofExample 21 utilizing 186A. MS (m/z) 517 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-cyanopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(186C)

The title compound (186C) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 10A ofExample 10 utilizing 186B and2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. MS (m/z) 763 [M+H]⁺.

Synthesis of5-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)nicotinamide(186D)

To a suspension of 186C (21 mg, 0.028 mmol) and K₂CO₃ (38 mg, 0.28 mmol)in DMSO, H₂O₂ (30 wt. % in H₂O, 0.028 mL, 0.28 mmol) was added to thesuspension slowly. After 10 minutes, the mixture was filtered andpurified by reverse phase HPLC to provide the title compound as amixture of atropisomers. ¹H NMR (400 MHz, Methanol-d4) ¹H NMR (400 MHz,Methanol-d4) δ 9.26 (t), 8.73 (t), 8.14 (dd), 7.31-7.14 (m), 7.09 (d),6.77 (tt), 6.72 (t), 6.68-6.59 (m), 6.49-6.30 (m), 5.35-5.25 (m),5.08-5.00 (m), 4.78-4.68 (m), 3.25 (d), 3.18-3.09 (m), 3.05-2.93 (m),2.65 (s), 2.44 (ddd), 1.39 (dq), 1.01 (h). MS (m/z) 781 [M+H]⁺.

Example 187

Synthesis of(S)—N—((S)-1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(187A)

To a solution of(S,Z)—N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(1.0 g, 2.717 mmol) and Cu(OTf)₂ (49.1 mg, 0.136 mmol) in DCM (10 mL)was added 3-fluorobenzyl zinc chloride (0.5M in THF, 7.6 mL, 3.803 mmol)dropwise over 7 minutes at 0° C. The reaction mixture was stirred at 0°C. for 1 hour, then quenched with saturated aqueous NH₄Cl and dilutedwith EtOAc. The organic layer was collected, and the aqueous layer wasextracted an additional time with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, concentrated, and purified by silicagel column chromatography to provide the title compound 187A. MS (m/z)476.93, 478.84, 480.79 [M+H]⁺.

Synthesis of(S)-1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethanamine (187B)

To a solution of(S)—N—((S)-1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(187A, 714.2 mg, 1.493 mmol) in MeOH (3.7 mL) was added HCl (4M in1,4-dioxane, 3.7 mL, 14.93 mmol). The reaction mixture was stirred atroom temperature for 30 minutes. Upon completion, the reaction mixturewas concentrated in vacuo to provide the title compound 187B, which wasused without purification. MS (m/z) 373.08, 374.92, 376.86 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate (187C)

To a solution of(S)-1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethanamine (187B,558.62 mg, 1.493 mmol) in DCM was added DIPEA (0.52 mL, 2.987 mmol). Thereaction mixture was cooled to 0° C., then Boc₂O (358.6 mg, 1.643 mmol)was added. The reaction mixture was warmed to room temperature andstirred at room temperature for 2.5 hours. Upon completion, the reactionmixture was concentrated in vacuo and purified by silica gel columnchromatography to provide the title compound 187C. MS (m/z) 472.71,474.68, 476.68 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate(187D)

A solution of (S)-tert-butyl(1-(3,6-dibromopyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate (187C,200.0 mg, 0.422 mmol) in 2-MeTHF was degassed by bubbling argon for 60seconds. To the degassed solution were added NEt₃ (0.18 mL, 1.268 mmol)and 2-methyl-3-butyn-2-ol (62 μL, 0.633 mmol) followed by CuI (2.4 mg,0.013 mmol) and PdCl₂(PPh₃)₂ (8.9 mg, 0.013 mmol). The reaction mixturewas stirred at room temperature for 30 minutes. Upon completion, thereaction mixture was diluted with water and extracted three times withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated in vacuo, and purified by silica gel column chromatographyto provide the title compound 187D. MS (m/z) 476.91, 478.83 [M+H]⁺.

Synthesis (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate(187E)

(S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate(187D, 189.7 mg, 0.397 mmol),N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(19D, 214.6 mg, 0.556 mmol), and PdCl₂(PPh₃)₂ (27.9 mg, 0.04 mmol) weretaken in 1,4-dioxane (10 mL) and NaHCO₃ (1 M in water, 1.19 mL, 1.19mmol). The resulting solution was degassed by bubbling argon for 5minutes, then the reaction flask was sealed and the reaction heated at150° C. for 20 minutes in a microwave reactor. Upon cooling, thereaction mixture was filtered, concentrated in vacuo, and purified bysilica gel column chromatography to provide the title compound 187E as amixture of atropisomers. MS (m/z) 655.92 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3-fluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(187F)

To a solution of (S)-tert-butyl(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate(187E, 257.3 mg, 0.392 mmol) in DCM (4 mL) was added TFA (4 mL). Thereaction mixture was stirred at room temperature for 1 hour 15 minutes.Upon completion, the reaction mixture was concentrated in vacuo toprovide the title compound 187F as a mixture of atropisomers which wasused without further purification. MS (m/z) 556.15 [M+H]⁺.

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(187G)

To a solution of(S)—N-(7-(2-(1-amino-2-(3-fluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide(187F, 218.0 mg, 0.392 mmol) in DMA (3 mL) was added NEt₃ (0.16 mL,1.176 mmol),2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (77.5 mg, 0.274 mmol), then HATU (104.4 mg, 0.274 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 15minutes. Upon completion, the reaction mixture was filtered and purifiedby reverse phase HPLC. Fractions containing the product were pooled andlyophilized to give the title compound 187G as a mixture ofatropisomers. ¹H NMR (400 MHz, Methanol-d₄) δ 8.80-8.70 (m), 7.65 (dd),7.51 (dd), 7.22-7.11 (m), 6.99 (d), 6.96-6.89 (m), 6.77 (t), 6.60-6.46(m), 6.15-6.07 (m), 5.37-5.25 (m), 5.02-4.93 (m), 4.84 (s), 4.80 (s),4.78 (s), 4.74 (s), 3.26 (s), 3.23 (s), 3.21-3.11 (m), 3.04-2.94 (m),2.82 (s), 2.61-2.39 (m), 1.65 (s), 1.50-1.35 (m), 1.19-1.12 (m),1.11-1.02 (m). MS (m/z) 820.12 [M+H]⁺.

Example 188

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)-2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(188)

The title compound (188) was prepared as a mixture of atropisomersaccording to the method presented for the synthesis of compound 187G ofExample 187 utilizing2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.72-8.62 (m), 7.65 (dd),7.57-7.44 (m), 7.33 (dd), 7.22-7.11 (m), 6.99 (d), 6.98-6.65 (m),6.61-6.46 (m), 6.14 (d), 6.13 (d), 5.31 (dd), 4.96 (dd), 4.79 (s), 4.74(s), 4.72 (s), 4.68 (s), 3.26 (s), 3.22 (s), 3.20-3.11 (m), 3.04-2.92(m), 2.83 (s), 2.55-2.39 (m), 1.65 (s), 1.45-1.32 (m), 1.15-1.07 (m),1.07-0.98 (m). MS (m/z) 802.15 [M+H]⁺.

Example 189

Synthesis of (S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(189)

The title compound (189) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (dd), 7.53 (dd), 7.18 (q),7.07 (d), 7.01-6.56 (m), 6.42 (d), 6.40-6.31 (m), 5.26 (dd), 5.04-4.86(m), 3.25 (s), 3.21 (s), 3.15 (dd), 3.04-2.93 (m), 1.64 (s). MS (m/z)783.1 [M+H]⁺.

Example 190

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1(7H)-yl)acetamide(190)

The title compound (190) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1(7H)-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.71 (dd), 7.53 (dd), 7.17 (q),7.09 (d), 6.82-6.69 (m), 6.68-6.59 (m), 6.42 (dd), 5.28-5.19 (m),5.01-4.92 (m), 4.69 (t), 4.52 (s), 3.92-3.78 (m), 3.25 (d), 3.20-3.09(m), 3.01 (s), 2.96 (dd), 2.73-2.59 (m), 1.64 (s). MS (m/z) 807.0[M+H]⁺.

Example 191

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide(191)

The title compound (191) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid. ¹H NMR(400 MHz, Methanol-d₄) δ 7.71 (dd), 7.53 (dd), 7.27 (d), 7.17 (d), 7.10(d), 6.80-6.72 (m), 6.67-6.58 (m), 6.52 (d), 6.45-6.33 (m), 6.24 (s),6.19 (s), 5.37-5.22 (m), 5.05-4.95 (m), 4.90 (d), 3.23 (d), 3.21-3.08(m), 3.05 (s), 3.03-2.93 (m), 1.64 (s), 1.59-1.47 (m), 1.04-0.90 (m),0.69-0.55 (m). MS (m/z) 791.0 [M+H]⁺.

Example 192

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetamide(192)

The title compound (192) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acid. ¹HNMR (400 MHz, Methanol-d₄) δ 7.63 (dd), 7.46 (dd), 7.13-7.03 (m),7.03-6.92 (m), 6.74-6.54 (m), 6.46 (d), 6.35 (d), 6.26 (d), 5.29-5.18(m), 5.04-4.89 (m), 3.47 (d), 3.43 (s), 3.22 (d), 3.18-3.08 (m), 2.97(s), 2.95-2.75 (m), 2.31 (s), 2.28 (s), 1.65 (s). MS (m/z) 761.5 [M+H]⁺.

Example 193

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(193)

The title compound (193) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(5-fluoro-1H-indol-3-yl)acetic acid. ¹H NMR (400MHz, Methanol-d₄) δ 7.63 (d), 7.53-7.43 (m), 7.34-7.24 (m), 7.18-7.06(m), 7.02 (dd), 6.91-6.77 (m), 6.74-6.64 (m), 6.64-6.56 (m), 6.49 (d),6.43-6.30 (m), 5.26-5.16 (m), 5.05-4.95 (m), 3.64-3.39 (m), 3.24 (s),3.23 (s), 3.14-2.80 (m), 1.64 (s). MS (m/z) 749.5 [M+H]⁺.

Example 194

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(194)

The title compound (194) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)aceticacid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.32-8.20 (m), 7.77-7.59 (m),7.56-7.49 (m), 7.17 (dd), 7.09-6.97 (m), 6.94 (d), 6.72 (d), 6.57-6.48(m), 6.38 (d), 6.29 (d), 5.29-5.17 (m), 5.12-5.00 (m), 4.18-4.14 (m),4.03 (d), 3.69-3.45 (m), 3.29-3.18 (m), 3.20-3.03 (m), 3.03-2.90 (m),1.65 (s). MS (m/z) 762.3 [M+H]⁺.

Example 195

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-phenylpropanamide(195)

The title compound (195) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-phenylpropanoic acid. ¹H NMR (400 MHz, Methanol-d₄)δ 7.71 (dd), 7.63-7.42 (m), 7.37-7.05 (m), 6.81-6.72 (m), 6.69 (d),6.67-6.52 (m), 6.49 (d), 6.47-6.39 (m), 6.35-6.24 (m), 5.28-5.22 (m),5.08-5.00 (m), 5.00-4.95 (m), 3.72-3.49 (m), 3.39 (s), 3.29-3.22 (m),3.18-2.95 (m), 2.91 (s), 2.88-2.84 (m), 2.81 (s), 1.64 (s), 1.35 (dd),1.32-1.19 (m). MS (m/z) 706.8 [M+H]⁺.

Example 196

Synthesis ofN—((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4,7-dimethyl-2-oxoindolin-3-yl)acetamide(196)

The title compound (196) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(4,7-dimethyl-2-oxoindolin-3-yl)acetic acid. ¹H NMR(400 MHz, Methanol-d₄) δ 7.69-7.61 (m), 7.61-7.41 (m), 7.16 (d),7.12-7.06 (m), 7.03 (d), 6.89-6.76 (m), 6.76-6.68 (m), 6.67 (d),6.64-6.54 (m), 6.49 (d), 6.43-6.36 (m), 6.34 (d), 5.18 (s), 5.14-5.06(m), 4.83-4.75 (m), 3.67-3.57 (m), 3.57-3.43 (m), 3.36 (s), 3.25 (dd),3.21-3.11 (m), 3.10-2.97 (m), 2.97-2.68 (m), 2.35-2.06 (m), 1.71-1.59(m). MS (m/z) 776.1 [M+H]⁺.

Example 197

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4-ethylpiperazin-1-yl)acetamide(197)

The title compound (197) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(4-ethylpiperazin-1-yl)acetic acid. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (dd), 7.54 (dd), 7.35 (d), 7.27 (d), 7.20 (d), 6.82(d), 6.80-6.73 (m), 6.69-6.62 (m), 6.50-6.37 (m), 5.47-5.39 (m), 5.07(dd), 3.40 (s), 3.27 (s), 3.23-2.87 (m), 1.63 (s), 1.35 (td). MS (m/z)729.0 [M+H]⁺.

Example 198

Synthesis of (S)-2-(benzo[d]isoxazol-3-yl)-N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(198)

The title compound (198) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(benzo[d]isoxazol-3-yl)acetic acid. ¹H NMR (400 MHz,Methanol-d₄) δ 7.72-7.63 (m), 7.60 (d), 7.59-7.49 (m), 7.37-7.30 (m),7.31-7.24 (m), 7.16 (d), 7.11 (d), 7.00 (d), 6.74-6.66 (m), 6.58 (d),6.47-6.38 (m), 5.30-5.22 (m), 5.07-4.95 (m), 3.93-3.76 (m), 3.24 (s),3.21-3.10 (m), 3.08-2.93 (m), 1.65 (s). MS (m/z) 733.2 [M+H]⁺.

Example 199

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(199)

The title compound (199) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid.¹H NMR (400 MHz, Methanol-d₄) δ 9.19 (s), 9.07 (s), 7.74 (dd), 7.63-7.50(m), 7.49-7.33 (m), 7.27 (s), 7.24-6.99 (m), 6.74-6.56 (m), 6.47-6.34(m), 5.38-5.29 (m), 5.22-4.91 (m), 4.03 (s), 3.25 (d), 3.23-3.19 (m),3.14 (s), 3.09-2.95 (m), 2.52-2.38 (m), 1.65 (s). MS (m/z) 761.1 [M+H]⁺.

Example 200

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(naphthalen-2-yl)acetamide(200)

The title compound (200) was prepared as a mixture of atropisomersaccording to the method presented in the synthesis of 10A in Example 10utilizing 19F and 2-(naphthalen-2-yl)acetic acid. ¹H NMR (400 MHz,Methanol-d₄) δ 7.86-7.69 (m), 7.69-7.62 (m), 7.59 (s), 7.55-7.49 (m),7.50-7.37 (m), 7.34 (d), 7.25-7.19 (m), 7.10 (dd), 6.99 (d), 6.84 (d),6.71-6.62 (m), 6.60-6.57 (m), 6.55 (dd), 6.47-6.34 (m), 5.24-5.16 (m),5.02 (t), 3.64-3.44 (m), 3.24 (s), 3.20 (s), 3.18-3.11 (m), 3.10 (d),3.03-2.93 (m), 1.64 (s). MS (m/z) 742.8 [M+H]⁺.

Example 201 Large scale preparation of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b-S,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(19G)

Synthesis of bicyclo[3.1.0]hexan-3-ol (19AB)

Et₂Zn (1M in hexane, 2.37 L, 2.37 mol) was added drop-wise to a solutionof compound 19AA (100 g, 1.19 mol) in DCM (800 ml) under N₂ at 0-5° C.The mixture was stirred at 0-5° C. for 30 min, then CH₂I₂ (636 g, 2.37mol) in DCM (200 ml) was added drop-wise in 1 h at 0-5° C. The resultingmixture was stirred at room temperature overnight. The mixture was addedslowly to ice-cold aq. NH₄Cl (1.5 L). The mixture was filtered. Theaqueous phase was extracted with DCM (2L×3). The combined organic layerwas dried over MgSO₄, concentrated in vacuo to give crude residue, whichwas purified by distillation (20 mmHg, 80° C.-82° C.) to give compound19AB. ¹H NMR: (400 MHz, CDCl₃) δ 4.35 (t, J=6.4 Hz, 1H), 2.10-2.06 (m,2H), 1.70 (d, J=14.0 Hz, 2H), 1.65 (s, 1H), 1.27-1.24 (m, 2H), 0.52-0.47(m, 2H).

Synthesis of bicyclo[3.1.0]hexan-3-one (19AC)

To a solution of K₂Cr₂O₇ (240 g, 0.82 mol) in H₂O (2 L), H₂SO₄ (240 g,2.45 mol) was added drop-wise at room temperature. The mixture wasstirred at room temperature for 1 h. The system was cooled to 0° C.,compound 19AB (100 g, 1.02 mol) in TBME (2 L) was added drop-wise. Thereaction mixture was stirred at room temperature for 4 h. The organiclayer was separated. The aqueous layer was extracted with TBME (1 L×3).The combined organic layer was dried over MgSO₄, filtered, concentratedin vacuo to give the crude product, which was purified by distillation(20 mmHg, 60° C.-62° C.) to give compound 19AC. ¹H NMR (400 MHz, CDCl₃)δ 2.57-2.52 (m, 2H), 2.13-2.08 (m, 2H), 1.50-1.47 (m, 2H), 0.88-0.85 (m,1H), 0.08-−0.01 (m, 1H).

Synthesis of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one (19AD)

To the solution of compound 19AC (100 g, 1.04 mol) in THF (1 L), LDA(700 ml, 1.05 mol, 1.5M in THF) was added drop-wise under N₂ over aperiod of 2 h. The resulting mixture was stirred 1 h at −78° C. Ethyldifluoroacetate (142 g, 1.14 mol) in THF (500 ml) was added drop-wiseover a period of 1 h and the reaction was stirred 1 h at −78° C. Thereaction was warmed to room temperature and stirred for 4 h. Thereaction was quenched by aqueous 1N HCl (1.5 L) and then partitionedbetween EA (1.0 L) and aqueous citric acid (300 ml). The organic layerwas separated and washed with brine. Solvents were removed in vacuo togive compound 19AD which was used for the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 6.17 (t, J=53.6 Hz, 1H),2.78-2.73 (m, 1H), 2.44-2.39 (m, 1H), 2.25-2.24 (m, 1H), 1.70-1.69 (m,1H), 1.22-1.14 (m, 1H), 0.31-0.27 (m, 1H).

Synthesis of3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole(19AE)

N₂H₄.H₂O (104 g, 2.08 mol) was added drop-wise in 30 min to the solutionof compound 19AD (380 g, 2.08 mol) in EtOH (4 L) at room temperature Themixture was stirred at reflux overnight. The mixture was concentrated invacuo then purified by silica gel column chromatography (PE:EA=10:1-5:1)to give compound 19AE. MS (m/z): 171.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ6.74 (t, J=55.6 Hz, 1H), 2.99-2.94 (m, 1H), 2.82-2.78 (m, 1H), 2.13-2.07(m, 2H), 1.14-1.08 (m, 1H), 0.30-0.27 (m, 1H).

Synthesis of ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(19AF)

To a solution of compound 19AE (201 g, 1.18 mol) in DMF (2 L), ethylbromoacetate (207 g, 1.24 mol) and Cs₂CO₃ (404 g, 1.24 mol) were addedin one portion at room temperature. The mixture was stirred at roomtemperature for 3 h. The mixture was poured into H₂O (4 L) and thenextracted with EA (2 L×3). The combined organic phase was washed withbrine (2 L×3), dried over MgSO₄, and concentrated in vacuo. The crudeproduct was purified by silica gel column chromatography(PE:EA=20:1-8:1) to obtain a mixture of N1 and N2 alkylation isomers. Anadditional purification from PE/EA (10/1) provided compound 19AF. MS(m/z): 257.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.61 (t, J=55.2 Hz, 1H),4.70 (dd, J=17.2, 11.2 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.91 (dd,J=16.0, 6.0 Hz, 1H), 2.72 (d, J=16.4 Hz, 1H), 2.17-2.09 (m, 1H), 1.28(t, J=7.2 Hz, 3H), 1.10-1.07 (m, 1H), 0.33-0.30 (m, 1H).

Synthesis of ethyl2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(19AG)

Compound 19AF (102 g, 0.39 mol) and celite 545 (390 g) were added tocyclohexane (3.5 L) and the mixture was stirred at 10° C. PDC (599 g,1.59 mol) was added in one portion followed by TBHP (289 ml, 1.59 mol)drop-wise in 30 min at 10° C. The reaction was slowly warmed to roomtemperature and stirred for 4 days. The reaction was filtered throughcelite and filter cake was washed with EtOAc (600 ml). The combinedorganic layer was stirred with saturated aqueous Na₂S₂O₃ (1000 ml) for 1h. The organic layer was separated and treated with half saturated FeSO₄(300 ml), washed with brine and dried over Na₂SO₄. Solvents were removedin vacuo to give crude product, which was additionally purified from PE(300 ml) to give compound 19AG. MS (m/z): 271.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 6.67 (t, J=54.8 Hz, 1H), 4.94 (s, 2H), 4.23 (q, J=7.2 Hz, 2H),2.79-2.78 (m, 1H), 2.59-2.56 (m, 1H), 1.70-1.65 (m, 2H), 1.28 (t, J=6.8Hz, 3H).

Synthesis of ethyl2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetate(19AH)

To compound 19AG (148.5 g, 0.55 mol) in DCM (2.0 L) was addedethane-1,2-dithiol (88.0 g, 0.94 mol) in one portion and the solutionwas stirred at room temperature. BF₃.2AcOH (175.8 g, 0.94 mol) was addedto above solution. The reaction was stirred at room temperature for 12h. The system was cooled to 0° C. and quenched with saturated aqueousNaHCO₃ (1000 ml). The organic layer was separated, washed with brine(500 ml) and dried over Na₂SO₄. Solvents were removed in vacuo and theresidue was purified by silica gel column chromatography(PE:EtOAc=30:1-10:1) to provide compound 19AH. MS (m/z): 347.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 6.61 (t, J=55.0 Hz, 1H), 4.90 (dd, J=17.2,10.8 Hz, 2H), 4.21 (q, J=4.8 Hz, 2H), 3.51-3.45 (m, 4H), 2.60-2.58 (m,1H), 2.43-2.42 (m, 1H), 1.29-1.23 (m, 4H), 0.63-0.61 (m, 1H).

Synthesis of ethyl2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(19AI)

A solution of DBDMH (99 g, 0.35 mol) in dry DCM (120 mL) was cooled to−78° C. in a teflon bottle. HF/Py (120 mL) was added drop-wise over aperiod of 30 min. The reaction was stirred at −78° C. for 30 min. Then asolution of compound 19AH (40 g, 0.12 mol) in dry DCM (80 mL) was addeddrop-wise over a period of 15 min at −78° C. The resulting mixture wasstirred for 30 min at this temperature, then slowly warm to −30° C. andstirred for 1.5 h. The reaction mixture was slowly poured into aq.NaHCO₃ (500 mL) and extracted with EA (500 mL×3). The combined organiclayer was washed with 10% aq. Na₂S₂O₃ (500 mL), brine (500 mL) and driedover Na₂SO₄. Solvents were removed in vacuo to afford the crude product,which was further purified by column chromatography (PE:EA=80:1 to 50:1)to give compound 19AI. MS (m/z): 293.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ6.63 (t, J=54.8 Hz, 1H), 4.83 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 2.48-2.45(m, 2H), 1.38-1.36 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.13-1.12 (m, 1H).

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (19AJ)

To a solution of compound 19AI (50 g, 171 mmol) in THF (87.5 mL) andMeOH (350 mL) was added the solution of LiOH (6.2 g, 257 mmol) in H₂O(350 mL). The mixture was stirred at 20° C. for 3 h. The mixture wasconcentrated to remove most of THF and MeOH, the aqueous was acidifiedby 1N HCl to adjust pH to 2-3, then extracted with EA (600 mL×2). Theorganic phase was separated and combined, dried over Na₂SO₄, filteredand concentrated in vacuum to give compound 19AJ.

2-((3b-S,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (19AK) and2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (19AL)

Compound 19AJ was separated by SFC (ChiralPak IC-10 u, 300×50 mm I.D.,mobile phase: CO₂ isopropanol (0.1% NH₃H₂O), 35% gradient, 200 mL minflow rate, 38° C. column temperature, detection at 220 nm) to givecompound 19AK (79.3 g) and 19AL (80.8 g). 19AK: MS (m/z): 265.0 [M+H]⁺;¹H NMR: (400 MHz, DMSO-d₆) δ 13.43 (br, 1H), 7.04 (t, J=54.0 Hz, 1H),4.99-4.87 (m, 2H), 2.62-2.57 (m, 2H), 1.46-1.41 (m, 1H), 0.96 (s, 1H).19AL: MS (m/z): 265.0 [M+H]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 13.42 (br,1H), 7.04 (t, J=54.0 Hz, 1H), 4.99-4.88 (m, 2H), 2.63-2.51 (m, 2H),1.46-1.41 (m, 1H), 0.97 (s, 1H).

Synthesis of 3,6-dibromo-2-(dibromomethyl)pyridine (5A)

To a stirred solution of 3,6-dibromo-2-methylpyridine (200.0 g, 797.06mmol) in CCl₄ (4000 mL), benzoyl peroxide (192.89 g, 797.06 mmol)followed by NBS (565.0 g, 3188.0 mmol) was added at room temperature.After addition was completed, the resulting reaction mixture was stirredin presence of white light 400 watt bulb at room temperature for 20 h.The reaction mixture was stirred at room temperature for 20 h. Thereaction mixture was filtered and washed with CCl₄ (2×800 mL). Thefiltrate was evaporated under reduced pressure which was furtherpurified by column chromatography on silica gel using 0-5% EA in hexaneas an eluent to afford compound 5A. MS (m/z): 409.66 [M+H]⁺.

Synthesis of 3,6-dibromopicolinaldehyde (5B)

To a solution of compound 5A (100.0 g, 244.67 mmol) in EtOH (1000 mL) at80° C., aqueous silver nitrate (103.9 g, 611.6 mmol, in 300 mL water)was added drop-wise, in 1 h at same temperature. After addition wascompleted, the resulting reaction mixture was stirred to reflux foranother 5 h. The reaction mixture was cooled to room temperature andfiltered. The filtrate was evaporated under reduced pressure and theresultant crude was diluted with water (1000 mL). The aqueous layer wasextracted with ethyl acetate (3×400 mL). The combined organic layerswere washed with water (2×400 mL), dried over sodium sulfate anddistilled off under reduced pressure gave compound 5B. MS (m/z): 265.96.[M+H]⁺

Synthesis of(S,Z)—N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(5C)

To a stirred solution of compound 5B (68.0 g, 256.7 mmol) in DCM (1400mL), copper (II) sulfate anhydrous (102.3 g, 641.75 mmol) was addedfollowed by (S)-2-methylpropane-2-sulfinamide (37.3 g, 308.0 mmol) atroom temperature. The resulting suspension was stirred at roomtemperature for 16 h. The reaction mixture was filtered and washed withDCM (100 mL). The eluent was evaporated under reduced pressure. Theresultant crude compound was recrystallized from diethyl ether (300 mL)to provide compound 5C. MS (m/z) 368.86 [M+H]⁺

Synthesis of(S)—N—((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(5D)

To a stirred solution of compound 5C (20.0 g, 54.33 mmol) in dry THF(300 mL), at −78° C. a solution of 3,5-difluorobenzylmagnesium bromide(260.8 mL, 0.2M in ether, 65.20 mmol) was added drop-wise in 1 h at −78°C. After addition was completed, the resulting reaction mixture wasstirred at −78° C. for 1 h. The reaction mixture was quenched withaqueous NH₄Cl (200 mL) at same temperature. Organic layer was separatedand aqueous layer was extracted with EtOAc (3×150 mL). The combinedorganic layers were washed with water (2×200 mL) and brine, dried overNa₂SO₄. The solvent was distilled off under reduced pressure and theresultant crude compound was purified by column chromatography onsilica-gel using 0-18% EA in hexane as an eluent to provide compound 5D.MS (m/z) 496.99 [M+H]⁺

Synthesis of(S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (5E)

To a solution of compound 5D (53 g, 107 mmol) in methanol (100 mL) wasslowly added 4 N HCl in dioxane (30 mL) at room temperature. Uponcompletion of the reaction, the volatiles were removed in vacuo. Theresulting solid was suspended in ether (200 mL) and collected byfiltration to provide compound 5E. MS (m/z) 393.17 [M+H]⁺

Synthesis of (S)-tert-butyl1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (14A)

To a suspension of compound 5E (5 g, 11.7 mmol) in DCM (50 mL) was addeddi-tert-butyl dicarbonate (3.1 g, 14 mmol) and triethylamine (2.4 g, 23mmol) at room temperature. Upon completion of the reaction, thevolatiles were removed in vacuo. The resulting residue was dissolved inEtOAc and washed with saturated aqueous ammonium chloride and brine. Theorganic layer was dried over sodium sulfate. The solvent was distilledoff under reduced pressure and the resultant crude compound was purifiedby column chromatography on silica-gel using ethyl acetate in hexane asan eluent to provide compound 14A. MS (m/z) 492.96 [M+H]⁺

Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(14B)

A solution of compound 14A (570 mg, 1.16 mmol), 3-methyl butynol (179μL, 1.74 mmol), CuI (6 mg, 0.03 mmol), Pd(PPh₃)₂Cl₂ (20 mg, 0.03 mmol)and triethylamine (0.5 mL) in THF (2 mL) was degassed with argon for 15min. The resulting solution was then heated at 35° C. for 2 h. Uponcompletion of the reaction, the mixture was filtered through a pad ofcelite and washed with ethyl acetate. The combined organic layers werewashed with aqueous NH₄Cl, water and brine, dried over Na₂SO₄. Thesolvent was distilled off under reduced pressure and the resultant crudecompound was purified by column chromatography on silica-gel using ethylacetate in hexane as an eluent to provide compound 14B. MS (m/z) 496.90[M+H]⁺

Synthesis of (S)-tert-butyl1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(19E)

To a flask of 14B (4000 mg, 8.075 mmol) in dioxane (150 mL) and DMF (75ml) was addedN-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide(3114 mg, 8.075 mmol), 1N sodium bicarbonate (20.2 ml, 20.2 mmol), anddichlorobis(tricyclohexylphosphine)palladium(II) (715.3 mg, 0.97 mmol).The reaction mixture was degassed by N₂ for 30 minutes and then moved tooil bath at 150° C. for 45 minutes. The reaction was cooled to roomtemperature and filtered. The filtrate was concentrated and dissolved inEtOAc (300 mL) and washed with brine twice. The organic layer was driedover sodium sulfate, concentrated and purified by column chromatographyon silica-gel using 50-90% EtOAc in hexane as an eluent to provide 19E.MS (m/z) 674.7 [M+H]⁺.

Synthesis of(S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamideTFA salt (19FF)

To a flask of 19E (1 g, 1.48 mmol), 10 mL of 40% of TFA indichloromethane was added to the flask. The mixture was neutralized byNaHCO₃ (aq) and extracted with EtOAc (200 mL twice). The organic layerwas concentrated and dried to provide 0.85 g of the desired product 19FFthat was used without further purification. MS (m/z) 574.4 [M+H]⁺.

Synthesis of (S)—N-(1-(3-(4chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(19G)

To a flask of 19FF (850 mg, 1.48 mmol) and DIEA (0.5 mL, 2.96 mmol) in20 mL DMF, 19AK (350 mg, 1.33 mmol) and HATU (507 mg, 1.33 mmol) in 10mL of DMF was added to the mixture slowly at 0° C. The mixture wasdiluted with EtOAc (300 mL) and washed with NaHCO₃. The organic layerwas concentrated and purify by column chromatography on silica-gel using50-80% EtOAc in hexane as an eluent to provide 19G. MS (m/z) 820.8[M+H]⁺.

Example 202

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet Compound X = 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X =10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/mlCompound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxidesolution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1mL (v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the present disclosure.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values is stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Also, the disclosure ofranges is intended as a continuous range including every value betweenthe minimum and maximum values plus the broadening of the range affordedby the use of the term “about” or “approximately.” Thus, recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. In one aspect, about a value includes and intends that value perse. For example, about x includes and intends x per se.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

Embodiments

Provided below are certain embodiments.

Embodiment I-1

A compound of formula I:

wherein:

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith one or more (e.g., 1 or 2) Z³ groups;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl or3-12 membered heterocycle of R¹ is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁴ groups;

R² is phenyl, 5-membered monocyclic-heteroaryl, 6-memberedmonocyclic-heteroaryl or (C₃-C₇)carbocycle, wherein any phenyl,5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or(C₃-C₇)carbocycle of R² is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁵ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl, or R^(3a) is selected from H,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl and R^(3b) is selected from —OH and—CN;

Z¹ is selected from 6-12 membered aryl, 5-14 membered heteroaryl and3-14 membered heterocycle, wherein any 6-12 membered aryl, 5-14 memberedheteroaryl and 3-14 membered heterocycle of Z¹ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b);

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n1), —OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1),—S(O)R^(p1), —S(O)₂OH, —S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1),—NR^(q1)R^(r1), —NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1),—NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1), —NR^(n6)S(O)₂OR^(p1),—NR^(n1)S(O)₂NR^(q1)R^(r1), NO₂, —C(O)R^(n1), —C(O)OR^(n1),—C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12membered heterocycle of Z^(1a) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(1c) is independently selected from (C₃-C₇)carbocycle, phenyl,5-6 membered monocyclic-heteroaryl, 3-7 membered heterocycle, halogen,—CN, —OR^(n2), —OC(O)R^(p2), —OC(O)NR^(q2)R^(r2), —SR^(n2), —S(O)R^(p2),—S(O)₂OH, —S(O)₂R^(p2), —S(O)₂NR^(q2)R^(r2), —NR^(q2)R^(r2),—NR^(n2)COR^(p2), —NR^(n2)CO₂R^(p2), —NR^(n2)CONR^(q2)R^(r2),—NR^(n2)S(O)₂R^(p2), —NR^(n2)S(O)₂OR^(p2), —NR^(n2)S(O₂NR^(q2)R^(r2),NO₂, —C(O)R^(n2), —C(O)OR^(n2), —C(O)NR^(q2)R^(r2), halophenyl, 5-6membered haloheteroaryl, 3-7 membered haloheterocycle and(C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R^(n1) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(n1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(n1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

each R^(p1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(p1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(p1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

R^(q1) and R^(r1) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(q1) or R^(r1) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d)groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynylof R^(q1) or R^(r1) is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1c) groups, or R^(q1) and R^(r1) together with thenitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle, wherein the 5, 6 or 7-membered heterocycle is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1p) or Z^(1d)groups;

each R^(n2) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R^(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 memberedmonocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

R^(q2) and R^(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R^(q2) and R^(r2) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

Z² is selected from (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,—C(O)R^(n3) and —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12membered C-linked-heteroaryl and 3-12 membered C-linked-heterocycle ofZ² is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4, or 5) Z^(2c) groups;

each Z^(2a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n4), —OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4),—S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4),—NR^(q4)R^(r4), —NR^(n4)COR^(p4), —NR^(n4)CO₂R^(p4),—NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4), —NR^(n4)S(O)₂OR^(p4),—NR^(n4)S(O)₂NR^(q4)R^(r4), NO₂, —C(O)R^(n4), —C(O)OR^(n4) and—C(O)NR^(q4)R^(r4), wherein any (C₃-C₇)carbocycle, 6-12 membered aryl,5-12 membered heteroaryl and 3-12 membered heterocycle of Z^(2a) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b)or Z^(2c) groups;

each Z^(2b) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z^(2c) is independently selected from halogen, —CN, —OR^(n4),—OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH,—S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), NO₂, —C(O)R^(n4),—C(O)OR^(n4) and —C(O)NR^(q4)R^(r4);

each R^(n3) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(n3) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₁-C₄)alkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl of R^(n3) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a) groups;

R^(q3) and R^(r3) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(q3) or R^(r3) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, andwherein any (C₁-C₄)alkyl and (C₂-C₄)alkenyl of R^(q3) or R^(r3) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a)groups, or R^(q3) and R^(r3) together with the nitrogen to which theyare attached form a heterocycle or heteroaryl, wherein the heterocycleor heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3,4 or 5) Z^(2b) or Z^(2c) groups;

each R^(n4) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each R^(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

R^(q4) and R^(r4) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each Z³ is independently selected from halogen, (C₁-C₄)alkyl, —OH, —CN,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, halogen, —CN, —OR^(n5), —OC(O)R^(p5),—OC(O)NR^(q5)R^(r5), —SR^(n5), —S(O)R^(p5), —S(O)₂OH, —S(O)₂R^(p5),—S(O)₂NR^(q5)R^(r5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5),—NR^(n5)CO₂R^(p5), —NR^(n5)CONR^(q5)R^(r5), —NR^(n5)S(O)₂R^(p5),—NR^(n5)S(O)₂OR^(p5), —NR^(n5)S(O)₂NR^(q5)R^(r5), NO₂, —C(O)R^(n5),—C(O)OR^(n5) and —C(O)NR^(q5)R^(r5), wherein any (C₃-C₇)carbocycle, ofZ⁴ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(4a) or Z^(4b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of Z⁴ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(4a) groups;

each Z^(4a) is independently selected from halogen, —CN, —OR^(n6),—OC(O)R^(p6), —OC(O)NR^(q6)R^(r6), —SR^(n6), —S(O)R^(p6), —S(O)₂OH,—S(O)₂R^(p6), —S(O)₂NR^(q6)R^(r6), —NR^(q6)R^(r6), —NR^(n6)COR^(p6),—NR^(n6)CO₂R^(p6), —NR^(n6)CONR^(q6)R^(r6), —NR^(n6)S(O)₂R^(p6),—NR^(n6)S(O)₂OR^(p6), —NR^(n6)S(O)₂NR^(q6)R^(r6), NO₂, —C(O)R^(n6),—C(O)OR^(n6) and —C(O)NR^(q6)R^(r6);

each Z^(4b) is independently selected from (C₁-C₄)alkyl, (C₂-C₄)alkenyl(C₂-C₄)alkynyl and (C₁-C₄)haloalkyl;

each R^(n5) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p5) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q5) and R^(r5) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(n6) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p6) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q6) and R^(r6) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each Z⁵ is independently selected from (C₁-C₆)alkyl, halogen, —CN and—OR^(n7),

wherein any (C₁-C₆)alkyl of Z⁵ is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) halogen; and

each R^(n7) is independently selected from H, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl and (C₃-C₇)carbocycle;

or a pharmaceutically acceptable salt thereof.

Embodiment I-2

The compound of Embodiment I-1 which is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof.

Embodiment I-3

The compound of Embodiment I-1 or Embodiment I-I-2 wherein R^(3a) andR^(3b) are each H.

Embodiment I-4

The compound of any one of Embodiments I-1 to I-3 wherein R² is phenylor a 5-membered monocyclic-heteroaryl, wherein any phenyl or 5-memberedmonocyclic-heteroaryl of R² is optionally substituted with one or moreZ⁵ groups.

Embodiment I-5

The compound of any one of Embodiments I-1 to I-3 wherein R² is phenyloptionally substituted with one or more Z⁵ groups.

Embodiment I-6

The compound of any one of Embodiments I-1 to I-5 wherein each Z⁵ ishalogen.

Embodiment I-7

The compound of any one of Embodiments I-1 to I-5 wherein each Z⁵ isfluoro.

Embodiment I-8

The compound of Embodiment I-1 or Embodiment I-2 wherein R² is3,5-difluorophenyl.

Embodiment I-9

The compound of Embodiment I-1 which is a compound of formula Ig:

or a pharmaceutically acceptable salt thereof.

Embodiment I-10

The compound of Embodiment I-1 which is a compound of formula Ie:

or a pharmaceutically acceptable salt thereof.

Embodiment I-11

The compound of any one of Embodiments I-1 to I-10 wherein A ispyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein any pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl of A is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith one or more Z³ groups.

Embodiment I-12

The compound of any one of Embodiments I-1 to I-10 wherein A ispyridinyl, wherein any pyridinyl of A is substituted with one Z¹ groupat the position shown, one Z² group, and optionally substituted with oneor more Z³ groups.

Embodiment I-13

The compound of any one of Embodiments I-1 to I-12 wherein A issubstituted with one Z¹ group at the position shown and one Z² group.

Embodiment I-14

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ isselected from:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment I-15

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ isselected from:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment I-16

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ is:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment I-17

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ is:

wherein Z^(3a) is selected from H and Z³.

Embodiment I-18

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ is:

wherein Z^(3a) is selected from H and Z³.

Embodiment I-19

The compound of any one of Embodiments I-14 to I-18 wherein each Z^(3a)is H.

Embodiment I-20

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from phenyl, 5-14 membered heteroaryl and 3-14 memberedheterocycle, wherein any phenyl, 5-14 membered heteroaryl and 3-14membered heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) or Z^(1b) groups.

Embodiment I-21

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment I-22

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle, wherein the 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle have 1-11carbon atoms and 1-5 heteroatoms in the ring system, and wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with oneor more Z^(1a) or Z^(1b) groups.

Embodiment I-23

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle, wherein any from 8-10 membered bicyclic-heteroaryland 8-10 membered bicyclic-heterocycle of Z¹ is optionally substitutedwith one or more Z^(1a) or Z^(1b) groups.

Embodiment I-24

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle, wherein the 8-10 membered bicyclic-heteroaryl and8-10 membered bicyclic-heterocycle have 3-9 carbon atoms and 1-5heteroatoms in the ring system, and wherein any 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle of Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment I-25

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl of Z¹ is optionallysubstituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment I-26

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl,1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl,4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl of Z¹ is optionallysubstituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment I-27

The compound of any one of Embodiments I-1 to I-26 wherein each Z^(1a)is independently selected from halogen, —OR^(n1), NR^(q1)R^(r1), and—C(O)NR^(q1)R^(r1).

Embodiment I-28

The compound of any one of Embodiments I-1 to I-26 wherein each Z^(1a)is independently selected from halogen and —C(O)NR^(q1)R^(r1).

Embodiment I-29

The compound of any one of Embodiments I-1 to I-26 wherein R^(n1),R^(q1) and R^(r1) are each H.

Embodiment I-30

The compound of any one of Embodiments I-1 to I-19 wherein Z¹ isselected from:

Embodiment I-31

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle and—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl and 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with one ormore Z^(2c) groups.

Embodiment I-32

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment I-33

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered andC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment I-34

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxo-pyridinyl,triazolyl, 1-oxoisoindolinyl, 1H-pyrrolo[2,3-b]pyridinyl and—C(O)NR^(q3)R^(r3), wherein any phenyl, pyridinyl, 2-oxopyridinyl,triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any 4-methylpentynyl of Z² is optionally substituted with one ormore Z^(2c) groups.

Embodiment I-35

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from 4-methylpentyn-1-yl, phenyl, pyridin-4-yl,1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl,1H-pyrrolo[2,3-b]pyridine-5-yl and —C(O)NR^(q3)R^(r3), wherein anyphenyl, pyridin-4-yl, 2-hydroxypyridin-2-yl, triazol-4-yl,1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridine-5-yl of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any 4-methylpentyn-1-yl of Z² is optionally substituted with oneor more Z^(2c) groups.

Embodiment I-36

The compound of any one of Embodiments I-1 to I-35 wherein Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment I-37

The compound of any one of Embodiments I-1 to I-36 wherein R^(q3) andR^(r3) are each H.

Embodiment I-38

The compound of any one of Embodiments I-1 to I-37 wherein each Z^(2c)is independently selected from halogen, —OR^(n4) and —C(O)NR^(q4)R^(r4).

Embodiment I-39

The compound of any one of Embodiments I-1 to I-38 wherein R^(n4) is Hor methyl, and R^(q4) and R^(r4) are each H.

Embodiment I-40

The compound of any one of Embodiments I-1 to I-30 wherein Z² isselected from:

Embodiment I-41

The compound of any one of Embodiments I-1 to I-10 wherein A-Z¹ isselected from:

Embodiment I-42

The compound of any one of Embodiments I-1 to I-41 wherein R¹ is a 5-12membered heteroaryl, wherein any 5-12 membered heteroaryl of R¹ isoptionally substituted with one or more Z⁴ groups.

Embodiment I-43

The compound of any one of Embodiments I-1 to I-41 wherein R¹ is a 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein any 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with one or more Z⁴groups.

Embodiment I-44

The compound of any one of Embodiments I-1 to I-41 wherein R¹ is a 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl have 4-10 carbon atoms and 1-5 heteroatoms in thering system, and wherein any 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl of R¹ is optionally substituted with oneor more Z⁴ groups.

Embodiment I-45

The compound of any one of Embodiments I-1 to I-41 wherein R¹ is a 8-12membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl contains at least one partially unsaturated ring,and wherein any 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

Embodiment I-46

The compound of any one of Embodiments I-1 to I-41 wherein R¹ has thefollowing formula IIb:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-8 memberedbicyclic heterocycle, wherein any 3-7 membered monocyclic-carbocycle,5-8 membered bicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or5-8 membered bicyclic heterocycle of C is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c), NZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴.

Embodiment I-47

The compound of any one of Embodiments I-1 to I-41 wherein R¹ has thefollowing formula IId:

wherein:

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle, 5-9 membered bicyclic-carbocycle, 3-7membered monocyclic-heterocycle or 5-9 membered bicyclic heterocycle,wherein any 3-7 membered monocyclic-carbocycle, 5-9 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-9 memberedbicyclic heterocycle of C is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

each Z^(4c) is independently selected from H or Z⁴.

Embodiment I-48

The compound of any one of Embodiments I-1 to I-41 wherein R¹ isselected from3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazolyl and4,5,6,7-tetrahydro-indazolyl, wherein any3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazolyl and4,5,6,7-tetrahydro-indazolyl of R¹ is optionally substituted with one ormore Z⁴ groups.

Embodiment I-49

The compound of any one of Embodiments I-1 to I-41 wherein R¹ isselected from3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and4,5,6,7-tetrahydro-indazol-1-yl, wherein any3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and4,5,6,7-tetrahydro-indazol-1-yl of R¹ is optionally substituted with oneor more Z⁴ groups.

Embodiment I-50

The compound of any one of Embodiments I-1 to I-49 wherein each Z⁴ isindependently selected from (C₁-C₆)alkyl and halogen, wherein any(C₁-C₆)alkyl of Z⁴ is optionally substituted with one or more halogen.

Embodiment I-51

The compound of any one of Embodiments I-1 to I-49 wherein each Z⁴ isindependently selected from fluoro, trifluoromethyl and difluoromethyl.

Embodiment I-52

The compound of any one of Embodiments I-1 to I-41 wherein R¹ isselected from:

Embodiment I-53

The compound of any one of Embodiments I-1 to I-41 wherein R¹ isselected from:

Embodiment I-54

The compound of Embodiment I-1 selected from:

and pharmaceutically acceptable salts thereof.

Embodiment I-55

A pharmaceutical composition comprising a compound of formula I asdescribed in any one of Embodiments I-1 to I-54, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment I-56

A method for treating a Retroviridae virus infection in a mammalcomprising administering a therapeutically effective amount of acompound of any one of Embodiments I-1 to I-54, or a pharmaceuticallyacceptable salt thereof, to the mammal.

Embodiment I-57

The method of claim 56 wherein the Retroviridae virus infection is anHIV virus infection.

Embodiment I-58

A method for treating an HIV infection in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I as described in any one of EmbodimentsI-1 to I-54, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof.

Embodiment I-59

A compound of formula I as described in any of Embodiments I-1 to I-54,or a pharmaceutically acceptable salt thereof for use in medicaltherapy.

Embodiment I-60

A compound of formula I as described in any one of Embodiments I-1 toI-54 or a pharmaceutically acceptable salt thereof, for the prophylacticor therapeutic treatment of a Retroviridae virus infection or an HIVvirus infection.

Embodiment I-61

The use of a compound as described in any one of Embodiments I-1 to I-54or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating a Retroviridae virus infection or an HIV virusinfection in a mammal.

Embodiment I-62

A compound or method as described herein.

Also provided below are certain embodiments.

Embodiment II-1

A compound of formula I:

wherein:

A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms,wherein the 6-membered monocyclic-heteroaryl is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith one or more (e.g., 1 or 2) Z³ groups;

R¹ is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 memberedheterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl or3-12 membered heterocycle of R¹ is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z⁴ groups;

R² is phenyl, 5-membered monocyclic-heteroaryl, 6-memberedmonocyclic-heteroaryl or (C₃-C₇)carbocycle, wherein any phenyl,5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or(C₃-C₇)carbocycle of R² is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁵ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl, or R^(3a) is selected from H,(C₁-C₃)alkyl and (C₁-C₃)haloalkyl and R^(3b) is selected from —OH and—CN;

Z¹ is selected from 6-12 membered aryl, 5-14 membered heteroaryl and3-14 membered heterocycle, wherein any 6-12 membered aryl, 5-14 memberedheteroaryl and 3-14 membered heterocycle of Z¹ is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1a) or Z^(1b);

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n1), —OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1),—S(O)R^(p1), —S(O)₂OH, —S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1),—NR^(q1)R^(r1), —NR^(n1)COR^(p1), —NR^(n1)CO₂R^(p1),—NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1), —NR^(n6)S(O)₂OR^(p1),—NR^(n1)S(O)₂NR^(q1)R^(r1), NO₂, —C(O)R^(n1), —C(O)OR^(n1),—C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12membered heterocycle of Z^(1a) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(1c) is independently selected from (C₃-C₇)carbocycle, phenyl,5-6 membered monocyclic-heteroaryl, 3-7 membered heterocycle, halogen,—CN, —OR^(n2), —OC(O)R^(p2), —OC(O)NR^(q2)R^(r2), —SR^(n2), —S(O)R^(p2),—S(O)₂OH, —S(O)₂R^(p2), —S(O)₂NR^(q2)R^(r2), —NR^(q2)R^(r2),—NR^(n2)COR^(p2), —NR^(n2)CO₂R^(p2), —NR^(n2)CONR^(q2)R^(r2),—NR^(n2)S(O)₂R^(p2), —NR^(n2)S(O)₂OR^(p2), —NR^(n2)S(O₂NR^(q2)R^(r2),NO₂, —C(O)R^(n2), —C(O)OR^(n2), —C(O)NR^(q2)R^(r2), halophenyl, 5-6membered haloheteroaryl, 3-7 membered haloheterocycle and(C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R^(n1) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(n1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(n1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

each R^(p1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(p1) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R^(p1) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c)groups;

R^(q1) and R^(r1) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6 memberedmonocyclic-heteroaryl and phenyl of R^(q1) or R^(r1) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d)groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynylof R^(q1) or R^(r1) is optionally substituted with one or more (e.g., 1,2, 3, 4 or 5) Z^(1c) groups, or R^(q1) and R^(r1) together with thenitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle, wherein the 5, 6 or 7-membered heterocycle is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d)groups;

each R^(n2) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R^(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, 5-6membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 memberedmonocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

R^(q2) and R^(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R^(q2) and R^(r2) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

Z² is selected from (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, 6-12 membered aryl,5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle,—C(O)R^(n3) and —C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12membered C-linked-heteroaryl and 3-12 membered C-linked-heterocycle ofZ² is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z² is optionally substituted with one or more (e.g.,1, 2, 3, 4, or 5) Z^(2c) groups;

each Z^(2a) is independently selected from (C₃-C₇)carbocycle, 6-12membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle,halogen, —CN, —OR^(n4), —OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4),—S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4),—NR^(q4)R^(r4), —NR^(n4)COR^(p4), —NR^(n4)CO₂R^(p4),—NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4), —NR^(n4)S(O)₂OR^(p4),—NR^(n4)S(O)₂NR^(q4)R^(r4), NO₂, —C(O)R^(n4), —C(O)OR^(n4) and—C(O)NR^(q4)R^(r4), wherein any (C₃-C₇)carbocycle, 6-12 membered aryl,5-12 membered heteroaryl and 3-12 membered heterocycle of Z^(2a) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b)or Z^(2c) groups;

each Z^(2b) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z^(2c) is independently selected from halogen, —CN, —OR^(n4),—OC(O)R^(p4), —OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH,—S(O)₂R^(p4), —S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂R^(q4)R^(r4), NO₂, —C(O)R^(n4),—C(O)OR^(n4) and —C(O)NR^(q4)R^(r4);

each R^(n3) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(n3) is optionally substituted with one ormore (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, and wherein any(C₁-C₄)alkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl of R^(n3) is optionallysubstituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a) groups;

R^(q3) and R^(r3) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12membered heteroaryl and 6-12 membered aryl, wherein any(C₃-C₇)carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryland 6-12 membered aryl of R^(q3) or R^(r3) is optionally substitutedwith one or more (e.g., 1, 2, 3, 4 or 5) Z^(2b) or Z^(2c) groups, andwherein any (C₁-C₄)alkyl and (C₂-C₄)alkenyl of R^(q3) or R^(r3) isoptionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z^(2a)groups, or R^(q3) and R^(r3) together with the nitrogen to which theyare attached form a heterocycle or heteroaryl, wherein the heterocycleor heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3,4 or 5) Z^(2b) or Z^(2c) groups;

each R^(n4) is independently selected from H, (C₁-C₄)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each R^(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

R^(q4) and R^(r4) are each independently selected from H, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl and (C₁-C₄)heteroalkyl;

each Z³ is independently selected from halogen, (C₁-C₄)alkyl, —OH, —CN,(C₁-C₄)heteroalkyl and (C₁-C₄)haloalkyl;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, halogen, —CN, —OR^(n5), —OC(O)R^(p5),—OC(O)NR^(q5)R^(r5), —SR^(n5), —S(O)R^(p5), —S(O)₂OH, —S(O)₂R^(p5),—S(O)₂NR^(q5)R^(r5), —NR^(q5)R^(r5), —NR^(n5)COR^(p5),—NR^(n5)CO₂R^(p5), —NR^(n5)CONR^(q5)R^(r5), —NR^(n5)S(O)₂R^(p5),—NR^(n5)S(O)₂OR^(p5), —NR^(n5)S(O)₂NR^(q5)R^(r5), NO₂, —C(O)R^(n5),—C(O)OR^(n5) and —C(O)NR^(q5)R^(r5), wherein any (C₃-C₇)carbocycle, ofZ⁴ is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5)Z^(4a) or Z^(4b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of Z⁴ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z^(4a) groups;

each Z^(4a) is independently selected from halogen, —CN, —OR^(n6),—OC(O)R^(p6), —OC(O)NR^(q6)R^(r6), —SR^(n6), —S(O)R^(p6), —S(O)₂OH,—S(O)₂R^(p6), —S(O)₂NR^(q6)R^(r6), —NR^(q6)R^(r6), —NR^(n6)COR^(p6),—NR^(n6)CO₂R^(p6), —NR^(n6)CONR^(q6)R^(r6), —NR^(n6)S(O)₂R^(p6),—NR^(n6)S(O)₂OR^(p6), —NR^(n6)S(O)₂NR^(q6)R^(r6), NO₂, —C(O)R^(n6),—C(O)OR^(n6) and —C(O)NR^(q6)R^(r6);

each Z^(4b) is independently selected from (C₁-C₄)alkyl, (C₂-C₄)alkenyl(C₂-C₄)alkynyl and (C₁-C₄)haloalkyl;

each R^(n5) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p5) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q5) and R^(r5) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(n6) is independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each R^(p6) is independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

R^(q6) and R^(r6) are each independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, (C₁-C₄)heteroalkyl, (C₂-C₄)alkenyl and (C₂-C₄)alkynyl;

each Z⁵ is independently selected from (C₁-C₆)alkyl, halogen, —CN and—OR^(n7), wherein any (C₁-C₆)alkyl of Z⁵ is optionally substituted withone or more (e.g., 1, 2, 3, 4 or 5) halogen; and

each R^(n7) is independently selected from H, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl and (C₃-C₇)carbocycle;

or a pharmaceutically acceptable salt thereof.

Embodiment II-2

The compound of Embodiment II-1 which is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof.

Embodiment II-3

The compound of Embodiment II-1 or Embodiment II-2 wherein R^(3a) andR^(3b) are each H.

Embodiment II-4

The compound of any one of Embodiments II-1-3 wherein R² is phenyl or a5-membered monocyclic-heteroaryl, wherein any phenyl or 5-memberedmonocyclic-heteroaryl of R² is optionally substituted with one or moreZ⁵ groups.

Embodiment II-5

The compound of any one of Embodiments II-1 to II-3 wherein R² is phenyloptionally substituted with one or more Z⁵ groups.

Embodiment II-6

The compound of any one of Embodiments II-1 to II-5 wherein each Z⁵ ishalogen.

Embodiment II-7

The compound of any one of Embodiments II-1 to II-5 wherein each Z⁵ isfluoro.

Embodiment II-8

The compound of Embodiment II-1 or Embodiment II-2 wherein R² is3,5-difluorophenyl.

Embodiment II-9

The compound of Embodiment II-1 which is a compound of formula Ig:

or a pharmaceutically acceptable salt thereof.

Embodiment II-10

The compound of Embodiment II-1 which is a compound of formula Ie:

or a pharmaceutically acceptable salt thereof.

Embodiment II-11

The compound of any one of Embodiments II-1 to II-10 wherein A ispyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein any pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl of A is substituted with one Z¹group at the position shown, one Z² group, and optionally substitutedwith one or more Z³ groups.

Embodiment II-12

The compound of any one of Embodiments II-1 to II-10 wherein A ispyridinyl, wherein any pyridinyl of A is substituted with one Z¹ groupat the position shown, one Z² group, and optionally substituted with oneor more Z³ groups.

Embodiment II-13

The compound of any one of Embodiments II-1 to II-12 wherein A issubstituted with one Z¹ group at the position shown and one Z² group.

Embodiment II-14

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ isselected from:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment II-15

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ isselected from:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment II-16

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ is:

wherein each Z^(3a) is independently selected from H and Z³.

Embodiment II-17

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ is:

wherein Z^(3a) is selected from H and Z³.

Embodiment II-18

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ is:

wherein Z^(3a) is selected from H and Z³.

Embodiment II-19

The compound of any one of Embodiments II-14 to II-18 wherein eachZ^(3a) is H.

Embodiment II-20

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from phenyl, 5-14 membered heteroaryl and 3-14 memberedheterocycle, wherein any phenyl, 5-14 membered heteroaryl and 3-14membered heterocycle of Z¹ is optionally substituted with one or moreZ^(1a) or Z^(1b) groups.

Embodiment II-21

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle wherein any phenyl, 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle of Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment II-22

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from phenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle, wherein the 5-6 memberedmonocyclic-heteroaryl, 8-10 membered bicyclic-heteroaryl, 8-10 memberedbicyclic-heterocycle and 9-12 membered tricyclic-heterocycle have 1-11carbon atoms and 1-5 heteroatoms in the ring system, and wherein anyphenyl, 5-6 membered monocyclic-heteroaryl, 8-10 memberedbicyclic-heteroaryl, 8-10 membered bicyclic-heterocycle and 9-12membered tricyclic-heterocycle of Z¹ is optionally substituted with oneor more Z^(1a) or Z^(1b) groups.

Embodiment II-23

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle, wherein any from 8-10 membered bicyclic-heteroaryland 8-10 membered bicyclic-heterocycle of Z¹ is optionally substitutedwith one or more Z^(1a) or Z^(1b) groups.

Embodiment II-24

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from 8-10 membered bicyclic-heteroaryl and 8-10 memberedbicyclic-heterocycle, wherein the 8-10 membered bicyclic-heteroaryl and8-10 membered bicyclic-heterocycle have 3-9 carbon atoms and 1-5heteroatoms in the ring system, and wherein any 8-10 memberedbicyclic-heteroaryl and 8-10 membered bicyclic-heterocycle of Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment II-25

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl,4-oxo-3,4-dihydroquinazolinyl,3-oxospiro[cyclopropane-1,1′-isoindolin]-yl, 1H-2-oxo-pyridinyl and2,4-dioxo-1,2,3,4-tetrahydrorquinazolinyl of Z¹ is optionallysubstituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment II-26

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl,1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl,4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl, wherein any phenyl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl,1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl,3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yland 2,4-dioxo-1,2,3,4-tetrahydrorquinazolin-8-yl of Z¹ is optionallysubstituted with one or more Z^(1a) or Z^(1b) groups.

Embodiment II-27

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ is1H-indazol-7-yl, wherein Z¹ is optionally substituted with one or moreZ^(1a) or Z^(1b) groups.

Embodiment II-28

The compound of any one of Embodiments II-1 to II-27 wherein each Z^(1a)is independently selected from halogen, —OR^(n1), NR^(q1)R^(r1), and—C(O)NR^(q1)R^(r1).

Embodiment II-29

The compound of any one of Embodiments II-1 to II-27 wherein each Z^(1a)is independently selected from halogen and —NR^(n1)S(O)₂R^(p1).

Embodiment II-30

The compound of any one of Embodiments II-1 to II-27 wherein each Z^(1b)is independently selected from (C₁-C₈)alkyl.

Embodiment II-31

The compound of any one of Embodiments II-1 to II-27 wherein each Z^(1a)is independently selected from halogen and NR^(n1)S(O)₂R^(p1) and eachZ^(1b) is independently selected from (C₁-C₈)alkyl.

Embodiment II-32

The compound of any one of Embodiments II-1 to II-27 wherein each Z^(1a)is independently selected from halogen and —C(O)NR^(q1)R^(r1).

Embodiment II-33

The compound of any one of Embodiments II-1 to II-27 wherein R^(n1),R^(q1) and R^(r1) are each H.

Embodiment II-34

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from:

Embodiment II-35

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ is

Embodiment II-36

The compound of any one of Embodiments II-1 to II-19 wherein Z¹ isselected from

Embodiment II-37

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from (C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl, 3-12 membered C-linked-heterocycle and—C(O)NR^(q3)R^(r3), wherein any 6-12 membered aryl, 5-12 memberedC-linked-heteroaryl and 3-12 membered C-linked-heterocycle of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any (C₂-C₈)alkynyl of Z² is optionally substituted with one ormore Z^(2c) groups.

Embodiment II-38

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein anyphenyl, 5-6 membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment II-39

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from (C₂-C₈)alkynyl, phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heterocycle and —C(O)NR^(q3)R^(r3), wherein the 5-6membered C-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl and 8-10 memberedC-linked-bicyclic-heterocycle have 1-9 carbon atoms and 1-4 heteroatomsin the ring system, and wherein any phenyl, 5-6 memberedC-linked-monocyclic-heteroaryl, 8-10 memberedC-linked-bicyclic-heteroaryl, 8-10 membered andC-linked-bicyclic-heterocycle of Z² is optionally substituted with oneor more Z^(2b) or Z^(2c) groups, and wherein any (C₂-C₈)alkynyl of Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment II-40

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxo-pyridinyl,triazolyl, 1-oxoisoindolinyl, 1H-pyrrolo[2,3-b]pyridinyl and—C(O)NR^(q3)R^(r3), wherein any phenyl, pyridinyl, 2-oxopyridinyl,triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any 4-methylpentynyl of Z² is optionally substituted with one ormore Z^(2c) groups.

Embodiment II-41

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from 4-methylpentyn-1-yl, phenyl, pyridin-4-yl,1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl,1H-pyrrolo[2,3-b]pyridine-5-yl and —C(O)NR^(q3)R^(r3), wherein anyphenyl, pyridin-4-yl, 2-hydroxypyridin-2-yl, triazol-4-yl,1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridine-5-yl of Z² isoptionally substituted with one or more Z^(2b) or Z^(2c) groups, andwherein any 4-methylpentyn-1-yl of Z² is optionally substituted with oneor more Z^(2c) groups.

Embodiment II-42

The compound of any one of Embodiments II-1 to II-41 wherein Z² isoptionally substituted with one or more Z^(2c) groups.

Embodiment II-43

The compound of any one of Embodiments II-1 to II-42 wherein R^(q3) andR^(r3) are each H.

Embodiment II-44

The compound of any one of Embodiments II-1 to II-43 wherein each Z^(2c)is independently selected from halogen, —OR^(n4) and —C(O)NR^(q4)R^(r4).

Embodiment II-45

The compound of any one of Embodiments II-1 to II-44 wherein R^(n4) is Hor methyl, and R^(q4) and R^(r4) are each H.

Embodiment II-46

The compound of any one of Embodiments II-1 to II-36 wherein Z² isselected from:

Embodiment II-47

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ isselected from:

Embodiment II-48

The compound of any one of Embodiments II-1 to II-10 wherein A-Z¹ isselected from:

Embodiment II-49

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is a5-12 membered heteroaryl, wherein any 5-12 membered heteroaryl of R¹ isoptionally substituted with one or more Z⁴ groups.

Embodiment II-50

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is a8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein any 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with one or more Z⁴groups.

Embodiment II-51

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is a8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl have 4-10 carbon atoms and 1-5 heteroatoms in thering system, and wherein any 8-12 membered bicyclic-heteroaryl or 8-12membered tricyclic-heteroaryl of R¹ is optionally substituted with oneor more Z⁴ groups.

Embodiment II-52

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is a8-12 membered bicyclic-heteroaryl or 8-12 membered tricyclic-heteroaryl,wherein the 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl contains at least one partially unsaturated ring,and wherein any 8-12 membered bicyclic-heteroaryl or 8-12 memberedtricyclic-heteroaryl of R¹ is optionally substituted with one or more(e.g., 1, 2, 3, 4 or 5) Z⁴ groups.

Embodiment II-53

The compound of any one of Embodiments II-1 to II-48 wherein R¹ has thefollowing formula IIb:

wherein:

C together with the two carbon atoms of ring B to which it is attachedforms a 3-7 membered monocyclic-carbocycle, 5-8 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-8 memberedbicyclic heterocycle, wherein any 3-7 membered monocyclic-carbocycle,5-8 membered bicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or5-8 membered bicyclic heterocycle of C is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

B is a 5 or 6 membered monocyclic-heteroaryl having 1, 2 or 3 nitrogenatoms;

V is C or N;

W is CZ^(4c), NZ^(4c) or N;

X is CZ^(4c), NZ^(4c) or N;

Y is CZ^(4c), N or absent;

the dashed bonds are selected from single bonds and double bonds,wherein the dashed bonds, V, W, X and Y are selected so that the 5 or 6membered monocyclic-heteroaryl B is aromatic; and

each Z^(4c) is independently selected from H or Z⁴.

Embodiment II-54

The compound of any one of Embodiments II-1 to II-48 wherein R¹ has thefollowing formula IId:

wherein:

C together with the two carbon atoms to which it is attached forms a 3-7membered monocyclic-carbocycle, 5-9 membered bicyclic-carbocycle, 3-7membered monocyclic-heterocycle or 5-9 membered bicyclic heterocycle,wherein any 3-7 membered monocyclic-carbocycle, 5-9 memberedbicyclic-carbocycle, 3-7 membered monocyclic-heterocycle or 5-9 memberedbicyclic heterocycle of C is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁴ groups; and

each Z^(4c) is independently selected from H or Z⁴.

Embodiment II-55

The compound of any one of Embodiments II-1 to II-48 wherein R¹ selectedfrom 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazolyland 4,5,6,7-tetrahydro-indazolyl, wherein any3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazolyl and4,5,6,7-tetrahydro-indazolyl of R¹ is optionally substituted with one ormore Z⁴ groups.

Embodiment 56

The compound of any one of Embodiments II-1 to II-48 wherein R¹ selectedfrom3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and4,5,6,7-tetrahydro-indazol-1-yl, wherein any3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and4,5,6,7-tetrahydro-indazol-1-yl of R¹ optionally substituted with one ormore Z⁴ groups.

Embodiment II-57

The compound of any one of Embodiments II-1 to II-56 wherein each Z⁴ isindependently selected from (C₁-C₆)alkyl and halogen, wherein any(C₁-C₆)alkyl of Z⁴ is optionally substituted with one or more halogen.

Embodiment II-58

The compound of any one of Embodiments II-1 to II-56 wherein each Z⁴ isindependently selected from fluoro, trifluoromethyl and difluoromethyl.

Embodiment II-59

The compound of any one of Embodiments II-1 to II-48 wherein R¹ isselected from:

Embodiment II-60

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is

Embodiment II-61

The compound of any one of Embodiments II-1 to II-48 wherein R¹ isselected from:

Embodiment II-62

The compound of any one of Embodiments II-1 to II-48 wherein R¹ is

Embodiment II-63

The compound of Embodiment II-1 selected from:

and pharmaceutically acceptable salts thereof.

Embodiment II-64

The compound of Embodiment II-1 selected from:

and pharmaceutically acceptable salts thereof.

Embodiment II-65

A pharmaceutical composition comprising a compound of formula I asdescribed in any one of Embodiments II-1 to II-64, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment II-66

A method for treating a Retroviridae virus infection in a mammalcomprising administering a therapeutically effective amount of acompound of any one of Embodiments II-1 to II-64, or a pharmaceuticallyacceptable salt thereof, to the mammal.

Embodiment II-67

The method of Embodiment II-66 wherein the Retroviridae virus infectionis an HIV virus infection.

Embodiment II-68

A method for treating an HIV infection in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I as described in any one of EmbodimentsII-1 to II-64, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof.

Embodiment II-69

A compound of formula I as described in any of Embodiments II-1 toII-44, or a pharmaceutically acceptable salt thereof for use in medicaltherapy.

Embodiment II-70

A compound of formula I as described in any one of Embodiments II-1 toII-44 or a pharmaceutically acceptable salt thereof, for theprophylactic or therapeutic treatment of a Retroviridae virus infectionor an HIV virus infection.

Embodiment II-71

The use of a compound as described in any one of Embodiments II-1 toII-44 or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for treating a Retroviridae virus infection or an HIVvirus infection in a mammal.

Embodiment II-72

A compound or method as described herein.

1. A compound of formula IIId:

wherein A¹ is CH, C—Z³, or nitrogen; A² is CH or nitrogen; R¹ is 6-12membered aryl, 5-12 membered heteroaryl, or 3-12 membered heterocycle,wherein any 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12membered heterocycle of R¹ is optionally substituted with 1, 2, 3, 4 or5 Z⁴ groups, wherein the Z⁴ groups are the same or different; eachR^(3a) and R^(3b) is independently H or (C₁-C₃)alkyl; Z¹ is 6-12membered aryl, 5-14 membered heteroaryl, or 3-14 membered heterocycle,wherein any 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14membered heterocycle of Z¹ is optionally substituted with 1, 2, 3, 4 or5 Z^(1a) or Z^(1b), wherein the Z^(1a) and Z^(1b) groups are the same ordifferent; each Z^(1a) is independently (C₃-C₇)carbocycle, 5-12 memberedheteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR^(n1),—OC(O)R^(p1), —OC(O)NR^(q1)R^(r1), —SR^(n1), —S(O)R^(p1), —S(O)₂OH,—S(O)₂R^(p1), —S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1), —NR^(n1)COR^(p1),—NR^(n1)CO₂R^(p1), —NR^(n1)CONR^(q1)R^(r1), —NR^(n1)S(O)₂R^(p1),—NR^(n1)S(O)₂OR^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —C(O)R^(n1),—C(O)OR^(n1), —C(O)NR^(q1)R^(r1) and —S(O)₂NR^(n1)COR^(p1), wherein any(C₃-C₇)carbocycle, 5-12 membered heteroaryl and 3-12 memberedheterocycle of Z^(1a) is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups are thesame or different; each Z^(1b) is independently (C₁-C₈)alkyl optionallysubstituted with 1, 2, 3, 4 or 5 halogen, which are the same ordifferent; each Z^(1c) is independently halogen, —CN, —OH, —NH₂,—C(O)NR^(q2)R^(r2), or (C₁-C₈)heteroalkyl; each Z^(1d) is independently(C₁-C₈)alkyl or (C₁-C₈)haloalkyl; each R^(n1) is independently H,(C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6membered monocyclic-heteroaryl, wherein any (C₃-C₇)carbocycle, 3-7membered heterocycle, or 5-6 membered monocyclic-heteroaryl of R^(n1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different, andwherein any (C₁-C₈)alkyl of R^(n1) is optionally substituted with 1, 2,3, 4 or 5 Z^(1c) groups, wherein the Z^(1c) groups are the same ordifferent; each R^(p1) is independently (C₁-C₈)alkyl, (C₃-C₇)carbocycle,3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl, whereinany (C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(p1) is optionally substituted with 1, 2, 3,4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d) groups arethe same or different, and wherein any (C₁-C₈)alkyl of R^(p1) isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups, wherein theZ^(1c) groups are the same or different; each R^(q1) and R^(r1) isindependently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle, 3-7 memberedheterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any(C₃-C₇)carbocycle, 3-7 membered heterocycle, or 5-6 memberedmonocyclic-heteroaryl of R^(q1) or R^(r1) is optionally substituted with1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups, wherein the Z^(1c) and Z^(1d)groups are the same or different, and wherein any (C₁-C₈)alkyl of R^(q1)or R^(r1) is optionally substituted with 1, 2, 3, 4 or 5 Z^(1c) groups,wherein the Z^(1c) groups are the same or different, or R^(q1) andR^(r1) together with the nitrogen to which they are attached form a 5, 6or 7-membered heterocycle, wherein the 5, 6 or 7-membered heterocycle isoptionally substituted with 1, 2, 3, 4 or 5 Z^(1c) or Z^(1d) groups,wherein the Z^(1c) and Z^(1d) groups are the same or different; eachR^(q2) and R^(r2) is independently H, (C₁-C₈)alkyl, (C₃-C₇)carbocycle,or R^(q2) and R^(r2) together with the nitrogen to which they areattached form a 5, 6, or 7-membered heterocycle; Z² is (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl,3-12 membered C-linked-heterocycle, —C(O)R^(n3), or —C(O)NR^(q3)R^(r3),wherein any 6-12 membered aryl, 5-12 membered C-linked-heteroaryl, or3-12 membered C-linked-heterocycle of Z² is optionally substituted with1, 2, 3, 4 or 5 Z^(2b) or Z^(2c) groups, wherein the Z^(2b) and Z^(2c)groups are the same or different, and wherein any (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of Z² is optionally substituted with 1, 2, 3, 4, or 5Z^(2c) groups, wherein the Z^(2c) groups are the same or different; eachR^(n3) is independently H or (C₁-C₄)alkyl; each R^(q3) and R^(r3) isindependently H or (C₁-C₄)alkyl; each Z^(2b) is independently oxo,(C₁-C₄)alkyl, (C₁-C₄)heteroalkyl or (C₁-C₄)haloalkyl; each Z^(2c) isindependently oxo, halogen, —CN, —OR^(n4), —OC(O)R^(p4),—OC(O)NR^(q4)R^(r4), —SR^(n4), —S(O)R^(p4), —S(O)₂OH, —S(O)₂R^(p4),—S(O)₂NR^(q4)R^(r4), —NR^(q4)R^(r4), —NR^(n4)COR^(p4),—NR^(n4)CO₂R^(p4), —NR^(n4)CONR^(q4)R^(r4), —NR^(n4)S(O)₂R^(p4),—NR^(n4)S(O)₂OR^(p4), —NR^(n4)S(O)₂NR^(q4)R^(r4), —NO₂, —C(O)R^(n4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4); each R^(n4) is independently H,(C₁-C₄)alkyl, (C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl; each R^(p4) isindependently (C₁-C₈)alkyl, (C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl;each R^(q4) and R^(r4) is independently H, (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, or (C₁-C₄)heteroalkyl; each Z³ is independently a(C₁-C₄)heteroalkyl; each Z⁴ is independently oxo, (C₁-C₈)alkyl,(C₃-C₇)carbocycle, halogen, —CN, —OR^(n5), —NR^(q5)R^(r5),—NR^(n5)COR^(p5), —NR^(n5)CO₂R^(p5), —C(O)R^(n5), —C(O)OR^(n5), or—C(O)NR^(q5)R^(r5), wherein any (C₃-C₇)carbocycle or (C₁-C₈)alkyl of Z⁴is optionally substituted with 1, 2, 3, 4 or 5 Z^(4a) groups, whereinthe Z^(4a) groups are the same or different; each Z^(4a) isindependently halogen, —CN, or —OR^(n6); each R^(n5), R^(p5), R^(q5),R^(r5), and R^(n6) is independently H or (C₁-C₄)alkyl; each Z⁵ isindependently halogen, which may be same or different; and n is 0, 1, 2,or 3; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, which is acompound of formula IIIe:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is

wherein C together with the two carbon atoms to which it is attachedforms a 3-7 membered monocyclic-carbocycle or 5-9 memberedbicyclic-carbocycle, wherein any 3-7 membered monocyclic-carbocycle or5-9 membered bicyclic-carbocycle of C is optionally substituted with 1,2, 3, 4 or 5 Z⁴ groups, wherein the Z⁴ groups are the same or different.4. (canceled)
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Z¹ is

wherein each Z^(1w) is independently Z^(1a), Z^(1b), or H.
 6. Thecompound of claim 5, or a pharmaceutically acceptable salt thereof,wherein: each Z^(1a) is independently halogen, —CN, —OR^(n1),—NR^(n1)S(O)₂R^(p1), —NR^(n1)S(O)₂NR^(q1)R^(r1), —NR^(q1)R^(r1),—NR^(n1)COR^(p1), —NR^(n1)CONR^(q1)R^(r1), or —NR^(n1)CO₂R^(p1); eachZ^(1b) is independently (C₁-C₈alkyl), wherein the (C₁-C₈alkyl) isoptionally substituted with 1, 2, or 3 halogen, which are the same ordifferent; and at least one of Z^(1w) is Z^(1a) or Z^(1b).
 7. (canceled)8. The compound of claim 6, or a pharmaceutically acceptable saltthereof, wherein each Z^(1a) is independently halogen,—NR^(n1)S(O)₂R^(p1), or —NR^(n1)S(O)₂NR^(q1)R^(r1).
 9. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein themoiety

wherein Z^(5a) is H or halogen. 10-13. (canceled)
 14. The compound ofclaim 13, or a pharmaceutically acceptable salt thereof, wherein A is:

15-16. (canceled)
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(3a) and R^(3b) are each H. 18-19.(canceled)
 20. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Z² is (C₂-C₈)alkynyl, optionally substituted with1, 2, or 3 Z^(2c) groups.
 21. The compound of claim 20, or apharmaceutically acceptable salt thereof, wherein each Z^(2c) isindependently halogen, —OR^(n4), NR^(q4)R^(r4), —NR^(n4)CO₂R^(p4),—C(O)OR^(n4), or —C(O)NR^(q4)R^(r4). 22-27. (canceled)
 28. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹optionally substituted with 1, 2, 3, 4, or 5 Z⁴ groups is


29. (canceled)
 30. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Z¹ is 8-10 membered bicyclic-heteroarylor 8-10 membered bicyclic-heterocycle, wherein any 8-10 memberedbicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle has 3-9 carbonatoms and 1-5 heteroatoms in the ring system, and wherein any 8-10membered bicyclic-heteroaryl or 8-10 membered bicyclic-heterocycle of Z¹is optionally substituted with 1, 2, 3, 4, or 5 Z^(1a) or Z^(1b) groups.31-45. (canceled)
 46. The compound of claim 44, or a pharmaceuticallyacceptable salt thereof, which is:


47. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 48. A pharmaceutical composition comprising acompound of claim 1, or a pharmaceutically acceptable salt thereof, andan additional therapeutic agent, wherein the additional therapeuticagent is an HIV protease inhibiting compound, an HIV non-nucleosideinhibitor of reverse transcriptase, an HIV nucleoside inhibitor ofreverse transcriptase, an HIV nucleotide inhibitor of reversetranscriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerizationinhibitor, or a non-catalytic site HIV integrase inhibitor andcombinations thereof.
 49. A method for treating a HIV infection in apatient in need thereof comprising administering a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, to the patient.
 50. A method for treating anHIV infection in a patient in need thereof comprising administering tothe patient a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of an additional therapeutic agent,wherein the additional therapeutic agent is an HIV protease inhibitingcompound, an HIV non-nucleoside inhibitor of reverse transcriptase, anHIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotideinhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, acapsid polymerization inhibitor, or a non-catalytic site HIV integrasesite inhibitor and combinations thereof. 51-54. (canceled)